Is ARHGAP31 p.Pro1215Ser (c.3643C>T) pathogenic?

ARHGAP31 p.Pro1215Ser (c.3643C>T) is classified Uncertain significance in ARHGAP31 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: ambiguous (0.3793); Very rare (popmax 0.00439%, sas); Associated with Inborn genetic diseases.

What condition is associated with ARHGAP31 p.Pro1215Ser (c.3643C>T)?

ARHGAP31 p.Pro1215Ser (c.3643C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ARHGAP31 p.Pro1215Ser (c.3643C>T) in the general population?

ARHGAP31 p.Pro1215Ser (c.3643C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about ARHGAP31 p.Pro1215Ser (c.3643C>T)?

AlphaMissense predicts ambiguous (score 0.3793) — an in-silico prediction, not a clinical call.

ARHGAP31 p.Pro1215Ser

c.3643C>T · VCV3940085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3793 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3793	ambiguous
REVEL	0.23	benign-leaning
SaProt	LLR -6.20	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 121 kb · p 1.9e-07 · regional, not allelic
Overall
CADD	24.9	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 0.00439% South Asian · 4/91,084 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000342% 5/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,771
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Pro1215Ser
Coding: c.3643C>T
MANE Select: NM_020754
Type: single nucleotide variant
Location: chr3:119415572 (GRCh38)
Gene constraint: LOEUF 0.38 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 43.32
Residue 1215: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARHGAP31 p.Pro1215Leu Uncertain significance ★★ ⚠ same residue
ARHGAP31 p.Pro1215Ala Uncertain significance ★ ⚠ same residue
ARHGAP31 p.Ala18Val Uncertain significance ★★ ⚠ same condition
ARHGAP31 p.Ala634Asp Uncertain significance ★★ ⚠ same condition
ARHGAP31 p.Arg1377Ser Uncertain significance ★★ ⚠ same condition
ARHGAP31 p.Arg199Gln Uncertain significance ★★ ⚠ same condition
ARHGAP31 p.Arg256Cys Uncertain significance ★★ ⚠ same condition
ARHGAP31 p.Arg478His Uncertain significance ★★ ⚠ same condition

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-pro1215ser (accessed [today's date]).

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