# NM_001012659.2(ARGFX):c.245G>A (p.Arg82His)

https://sugi.bio/variant/argfx-p-arg82his

## Summary

**ARGFX p.Arg82His (c.245G>A)** is classified **Uncertain significance** in ARGFX (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-10). AlphaMissense: ambiguous (0.4471); Ultra-rare (popmax 0.0433%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs531332897 · 1 submitter · AlphaMissense ambiguous · ultra-rare (popmax 0.0433%, amr)

## For patients & families {#patients}

This is a change in the ARGFX 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 | [ARGFX](https://sugi.bio/atlas/gene/ARGFX/) |
| Protein change (HGVS p.) | p.Arg82His |
| Coding change (HGVS c.) | c.245G>A |
| MANE Select transcript | [NM_001012659](https://www.ncbi.nlm.nih.gov/nuccore/NM_001012659) |
| dbSNP | [rs531332897](https://www.ncbi.nlm.nih.gov/snp/rs531332897/) |
| Variant type | single nucleotide variant |
| Location | chr3:121584941-121584941 (GRCh38) |
| ClinVar | [VCV2371680](https://www.ncbi.nlm.nih.gov/clinvar/variation/2371680/) |

**All HGVS expressions:** `NC_000003.11:g.121303788G>A`, `NC_000003.12:g.121584941G>A`, `NM_001012659.2:c.245G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4471) — no call either way
- REVEL 0.384 (indeterminate)
- SaProt LLR -7.344 (tolerated)
- Conservation: phyloP 0.534, GERP 0.672 — weakly conserved position
- CADD: **PHRED 15.89**. 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 0.87** across the covering region of the MANE Select transcript (121,570,714–121,586,597), spanning 15,883 bp. Chi-square p 0.019. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.25 acceptor loss), 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 **0.0433%** (amr) · FAF95 0.0353% · FAF99 0.0341% · 26/59,980 in the highest group · 491/1,613,368 alleles overall — ultra-rare (popmax 0.0433%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0433% | 2,307 |
| European (non-Finnish) | 0.0382% | 2,616 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,918 |
| African / African-American | 0.00401% | 24,961 |
| East Asian | 0.00223% | 44,882 |
| South Asian | 0.0022% | 45,500 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,030 |

*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}

**ARGFX** population constraint: LOEUF 1.843, pLI 0.00021015, missense-Z 1.1853. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **82** lies in a DNA-binding region.

AlphaFold model confidence (whole protein): pLDDT 57.78, 18% of residues very-high.

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

*Describes the biological roles of ARGFX (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:** ARGFX's established molecular role includes sequence-specific double-stranded DNA binding. p.Arg82His falls in a DNA-binding region.


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

**Molecular function:** sequence-specific double-stranded DNA binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-10 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ARGFX variant pages (same residue, condition, or type): [ARGFX p.Ala190Glu](/variant/argfx-p-ala190glu), [ARGFX p.Arg114Thr](/variant/argfx-p-arg114thr), [ARGFX p.Arg129Gln](/variant/argfx-p-arg129gln), [ARGFX p.Arg129Trp](/variant/argfx-p-arg129trp), [ARGFX p.Arg130Gln](/variant/argfx-p-arg130gln), [ARGFX p.Arg212Met](/variant/argfx-p-arg212met), [ARGFX p.Asn188Ile](/variant/argfx-p-asn188ile), [ARGFX p.Asp238Tyr](/variant/argfx-p-asp238tyr).

### 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 2371680). 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.*