Is ARHGAP31 p.Ser1374Pro (c.4120T>C) pathogenic?

ARHGAP31 p.Ser1374Pro (c.4120T>C) is classified Uncertain significance in ARHGAP31 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-26). AlphaMissense: likely pathogenic (0.7615); Very rare (popmax 0.00333%, amr).

How common is ARHGAP31 p.Ser1374Pro (c.4120T>C) in the general population?

ARHGAP31 p.Ser1374Pro (c.4120T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ARHGAP31 p.Ser1374Pro (c.4120T>C)?

AlphaMissense predicts likely pathogenic (score 0.7615) — an in-silico prediction, not a clinical call.

ARHGAP31 p.Ser1374Pro

c.4120T>C · rs748087375 · VCV1963750

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7615 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7615	likely pathogenic
REVEL	0.193	benign-leaning
SaProt	LLR -7.16	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 121 kb · p 1.9e-07 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,030 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000137% 2/1,461,894 alleles · very rare

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: ARHGAP31
Protein: p.Ser1374Pro
Coding: c.4120T>C
MANE Select: NM_020754
dbSNP: rs748087375
Type: single nucleotide variant
Location: chr3:119416049 (GRCh38)
Gene constraint: LOEUF 0.38 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 43.32

Full ARHGAP31 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP31 p.Ser1374Phe Uncertain significance ★ ⚠ same residue
ARHGAP31 p.Ala18Val Uncertain significance ★★ ⚠ same type
ARHGAP31 p.Ala634Asp Uncertain significance ★★ ⚠ same type
ARHGAP31 p.Arg1377Ser Uncertain significance ★★ ⚠ same type
ARHGAP31 p.Arg199Gln Uncertain significance ★★ ⚠ same type
ARHGAP31 p.Arg256Cys Uncertain significance ★★ ⚠ same type
ARHGAP31 p.Arg426Gly Uncertain significance ★★ ⚠ same type
ARHGAP31 p.Arg478His 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/arhgap31-p-ser1374pro (accessed [today's date]).

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