# NM_130810.4(DNAAF4):c.271G>T (p.Val91Phe)

https://sugi.bio/variant/dnaaf4-p-val91phe

## Summary

**DNAAF4 p.Val91Phe (c.271G>T)** is classified **Uncertain significance** in DNAAF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-20). AlphaMissense: likely benign (0.0848); Very rare (popmax 0.00179%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs17819126 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00179%, nfe)

## For patients & families {#patients}

This is a change in the DNAAF4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [DNAAF4](https://sugi.bio/atlas/gene/DNAAF4/) |
| Protein change (HGVS p.) | p.Val91Phe |
| Coding change (HGVS c.) | c.271G>T |
| MANE Select transcript | [NM_130810](https://www.ncbi.nlm.nih.gov/nuccore/NM_130810) |
| dbSNP | [rs17819126](https://www.ncbi.nlm.nih.gov/snp/rs17819126/) |
| Variant type | single nucleotide variant |
| Location | chr15:55497712-55497712 (GRCh38) |
| ClinVar | [VCV1013641](https://www.ncbi.nlm.nih.gov/clinvar/variation/1013641/) |

**All HGVS expressions:** `NC_000015.10:g.55497712C>A`, `NC_000015.9:g.55789910C>A`, `NG_021213.1:g.15523G>T`, `NM_001033559.3:c.271G>T`, `NM_001033560.2:c.271G>T`, `NM_130810.4:c.271G>T`, `NR_037923.1:n.526G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0848)
- REVEL 0.07 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -10.268 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- SpliceAI predicts **donor gain** (Δ 0.29) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.775, GERP 1.2, phastCons 0.214 — weakly conserved position
- CADD: **PHRED 21.5**. 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.*
- Regional missense constraint: **o/e 1.18** across the covering region of the MANE Select transcript (55,430,673–55,498,329), spanning 67,656 bp. Chi-square p 7.4e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.05**, acceptor gain **0.00**, donor gain **0.29**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.29**.
- Population frequency (gnomAD v4.1): grpmax **0.00179%** (nfe) · FAF95 0.00115% · FAF99 0.000974% · 21/1,175,550 in the highest group · 22/1,600,004 alleles overall — very rare (popmax 0.00179%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00179% | 55,979 |
| Remaining individuals (not grpmax-eligible) | 0.00162% | 61,854 |

*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}

**DNAAF4** population constraint: LOEUF 1.018, pLI 4.0683e-10, missense-Z -1.2189. *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):

- **primary ciliary dyskinesia 25** — Definitive (AR)

## Protein context {#protein}

Residue **91** lies in a UniProt-annotated variant site (in); the 'mediates interaction with esr1 and stub1' region.

AlphaFold model confidence (whole protein): pLDDT 84.00, 53% of residues very-high.

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

*Describes the biological roles of DNAAF4 (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:** DNAAF4's established molecular role includes nuclear estrogen receptor binding. p.Val91Phe falls in the mediates interaction with esr1 and stub1 region.


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

**Molecular function:** nuclear estrogen receptor binding.

**Biological process:** cilium movement, determination of left/right symmetry, regulation of intracellular estrogen receptor signaling pathway, outer dynein arm assembly, inner dynein arm assembly, regulation of proteasomal protein catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-07-20.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-07-20 |

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

## Similar variants {#similar}

Related DNAAF4 variant pages (same residue, condition, or type): [DNAAF4 p.Val91Ile](/variant/dnaaf4-p-val91ile), [DNAAF4 c.1047+1G>A](/variant/dnaaf4-c-1047-plus-1g-a), [DNAAF4 c.1153+1G>A](/variant/dnaaf4-c-1153-plus-1g-a), [DNAAF4 c.405+1G>A](/variant/dnaaf4-c-405-plus-1g-a), [DNAAF4 p.Arg245Ter](/variant/dnaaf4-p-arg245ter), [DNAAF4 p.Arg270Ter](/variant/dnaaf4-p-arg270ter), [DNAAF4 p.Arg330Trp](/variant/dnaaf4-p-arg330trp), [DNAAF4 p.Arg371Ter](/variant/dnaaf4-p-arg371ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1013641). 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.*