# NM_002907.4(RECQL):c.993G>A (p.Thr331=)

https://sugi.bio/variant/recql-p-thr331

## Summary

**RECQL p.Thr331= (c.993G>A)** is classified **Likely benign** in RECQL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-18). Very rare (popmax 0.00644%, nfe).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs764491255 · 3 submitters · very rare (popmax 0.00644%, nfe)

## For patients & families {#patients}

This is a change in the RECQL gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RECQL](https://sugi.bio/atlas/gene/RECQL/) |
| Protein change (HGVS p.) | p.Thr331= |
| Coding change (HGVS c.) | c.993G>A |
| MANE Select transcript | [NM_002907](https://www.ncbi.nlm.nih.gov/nuccore/NM_002907) |
| dbSNP | [rs764491255](https://www.ncbi.nlm.nih.gov/snp/rs764491255/) |
| Variant type | single nucleotide variant |
| Location | chr12:21475781-21475781 (GRCh38) |
| ClinVar | [VCV514891](https://www.ncbi.nlm.nih.gov/clinvar/variation/514891/) |

**All HGVS expressions:** `NC_000012.11:g.21628715C>T`, `NC_000012.12:g.21475781C>T`, `NM_002907.4:c.993G>A`, `NM_032941.3:c.993G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -4.087, GERP -3.74 — fast-evolving / accelerated position
- CADD: **PHRED 5.1**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.23 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00644%** (nfe) · FAF95 0.00528% · FAF99 0.00482% · 76/1,179,310 in the highest group · 83/1,612,950 alleles overall — very rare (popmax 0.00644%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00644% | 15,517 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,812 |
| Admixed American | 0.00334% | 29,973 |
| East Asian | 0.00223% | 44,866 |
| African / African-American | 0.00134% | 74,862 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**RECQL** population constraint: LOEUF 1.235, pLI 1.0681e-19, missense-Z 1.0791; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hereditary breast carcinoma** — Disputed (AD)
- **familial ovarian cancer** — No Known Disease Relationship (AD)

## Protein context {#protein}

Residue **331** lies in the helicase c-terminal domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 86.55, 69% of residues very-high.

**7 experimental structure(s)** (PDB): [2V1X](https://www.rcsb.org/structure/2V1X), [2WWY](https://www.rcsb.org/structure/2WWY), [4U7D](https://www.rcsb.org/structure/4U7D), [6JTZ](https://www.rcsb.org/structure/6JTZ), [8YRS](https://www.rcsb.org/structure/8YRS), [9I22](https://www.rcsb.org/structure/9I22).

## What this gene does {#gene-function}

*Describes the biological roles of RECQL (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** RECQL's established molecular role includes DNA helicase activity. p.Thr331= falls in the helicase c-terminal domain.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** DNA helicase activity, double-stranded DNA helicase activity, 3'-5' DNA helicase activity, DNA/DNA annealing activity.

**Biological process:** replication fork processing.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-18.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-07-27 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-02-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-18 |

**Reported phenotype names (ClinVar):** not provided, not specified, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related RECQL variant pages (same residue, condition, or type): [RECQL p.Thr331Met](/variant/recql-p-thr331met), [RECQL p.Thr331Pro](/variant/recql-p-thr331pro), [RECQL c.1098+1G>A](/variant/recql-c-1098-plus-1g-a), [RECQL c.1216+3A>G](/variant/recql-c-1216-plus-3a-g), [RECQL c.1217-3C>T](/variant/recql-c-1217-minus-3c-t), [RECQL c.1355+1G>A](/variant/recql-c-1355-plus-1g-a), [RECQL c.1356-12A>G](/variant/recql-c-1356-minus-12a-g), [RECQL c.1667+5G>C](/variant/recql-c-1667-plus-5g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 514891). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*