Is ARGFX p.Val261Ile (c.781G>A) pathogenic?

ARGFX p.Val261Ile (c.781G>A) is classified Uncertain significance in ARGFX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.0829); Ultra-rare (popmax 0.0472%, sas).

How common is ARGFX p.Val261Ile (c.781G>A) in the general population?

ARGFX p.Val261Ile (c.781G>A) is ultra-rare (popmax 0.0472%, sas) (gnomAD).

What do computational predictors say about ARGFX p.Val261Ile (c.781G>A)?

AlphaMissense predicts likely benign (score 0.0829) — an in-silico prediction, not a clinical call.

ARGFX p.Val261Ile

c.781G>A · VCV3937659

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0829 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0472%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0829	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -6.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.74	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -1.8	GERP -3.1
Regional constraint	o/e 0.87	unconstrained · MANE · 16 kb · p 0.019 · regional, not allelic
Overall
CADD	0.089	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0472% South Asian · 43/91,082 alleles

Filtering AF 0.036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0321%

Overall 0.00341% 55/1,614,158 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0472%	2,118
Admixed American	0.0183%	5,456
Middle Eastern	0.0165%	6,062

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ARGFX
Protein: p.Val261Ile
Coding: c.781G>A
MANE Select: NM_001012659
Type: single nucleotide variant
Location: chr3:121586433 (GRCh38)
Gene constraint: LOEUF 1.843 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.78

Full ARGFX gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARGFX p.Ala190Glu Uncertain significance ★ ⚠ same type
ARGFX p.Arg114Thr Uncertain significance ★ ⚠ same type
ARGFX p.Arg129Gln Uncertain significance ★ ⚠ same type
ARGFX p.Arg129Trp Uncertain significance ★ ⚠ same type
ARGFX p.Arg130Gln Uncertain significance ★ ⚠ same type
ARGFX p.Arg212Met Uncertain significance ★ ⚠ same type
ARGFX p.Arg82His Uncertain significance ★ ⚠ same type
ARGFX p.Asn188Ile Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/argfx-p-val261ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown