Is ARHGAP8 p.Ser340Phe (c.1019C>T) pathogenic?

ARHGAP8 p.Ser340Phe (c.1019C>T) is classified Uncertain significance in ARHGAP8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-02). AlphaMissense: ambiguous (0.3542); Ultra-rare (popmax 0.0439%, nfe).

How common is ARHGAP8 p.Ser340Phe (c.1019C>T) in the general population?

ARHGAP8 p.Ser340Phe (c.1019C>T) is ultra-rare (popmax 0.0439%, nfe) (gnomAD).

What do computational predictors say about ARHGAP8 p.Ser340Phe (c.1019C>T)?

AlphaMissense predicts ambiguous (score 0.3542) — an in-silico prediction, not a clinical call.

ARHGAP8 p.Ser340Phe

c.1019C>T · rs143652701 · VCV3128926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3542 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0439%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3542	ambiguous
REVEL	0.256	benign-leaning
SaProt	LLR -9.40	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 4.2	GERP 0.033, phastCons 1
Regional constraint	o/e 1.62	unconstrained · MANE · 76 kb · p 4.7e-50 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S371F vs ClinVar S340F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0439% European (non-Finnish) · 518/1,179,182 alleles

Filtering AF 0.0408% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0395%

Overall 0.0342% 552/1,612,774 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0439%	2,276
Finnishnot grpmax-eligible	0.0297%	3,369
Middle Eastern	0.0165%	6,050
Remaining individualsnot grpmax-eligible	0.0112%	8,919
African / African-American	0.00533%	18,755
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,516
Admixed American	0.00167%	59,934
South Asian	0.0011%	90,880

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: ARHGAP8
Protein: p.Ser340Phe
Coding: c.1019C>T
MANE Select: NM_181335
dbSNP: rs143652701
Type: single nucleotide variant
Location: chr22:44862312 (GRCh38)
Gene constraint: LOEUF 1.648 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.51
Residue 340: the rho-gap domain

Full ARHGAP8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP8 p.Ile374= Benign ★★ same type
ARHGAP8 p.Pro176Leu Benign ★★ same type
ARHGAP8 p.Ala235Thr Uncertain significance ★ ⚠ same type
ARHGAP8 p.Ala362Thr Uncertain significance ★ ⚠ same type
ARHGAP8 p.Ala386Val Uncertain significance ★ ⚠ same type
ARHGAP8 p.Ala413Val Uncertain significance ★ ⚠ same type
ARHGAP8 p.Arg162Gly Uncertain significance ★ ⚠ same type
ARHGAP8 p.Arg185Gln 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/arhgap8-p-ser340phe (accessed [today's date]).

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