Is ARHGAP5 p.Ser683Phe (c.2048C>T) pathogenic?

ARHGAP5 p.Ser683Phe (c.2048C>T) is classified Uncertain significance in ARHGAP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely benign (0.1513); Low-frequency (popmax 1.14%, mid).

How common is ARHGAP5 p.Ser683Phe (c.2048C>T) in the general population?

ARHGAP5 p.Ser683Phe (c.2048C>T) is low-frequency (popmax 1.14%, mid) (gnomAD).

What do computational predictors say about ARHGAP5 p.Ser683Phe (c.2048C>T)?

AlphaMissense predicts likely benign (score 0.1513) — an in-silico prediction, not a clinical call.

ARHGAP5 p.Ser683Phe

c.2048C>T · rs141134108 · VCV2230260

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1513 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.14%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1513	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 4.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 2,789 bp · p 4.8e-06 · regional, not allelic
Overall
CADD	24.0	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 1.14% Middle Eastern · 69/6,060 alleles

Filtering AF 0.923% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.844%

Overall 0.0533% 860/1,613,554 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.14%	88
Ashkenazi Jewishnot grpmax-eligible	0.639%	156
Remaining individualsnot grpmax-eligible	0.0896%	1,116
European (non-Finnish)	0.0424%	2,359
Admixed American	0.0317%	3,156
African / African-American	0.016%	6,248
South Asian	0.0132%	7,582
Finnishnot grpmax-eligible	0.00469%	21,339

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: ARHGAP5
Protein: p.Ser683Phe
Coding: c.2048C>T
MANE Select: NM_001030055
dbSNP: rs141134108
Type: single nucleotide variant
Location: chr14:32092717 (GRCh38)
Gene constraint: LOEUF 0.295 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.37 · 3 PDB
Residue 683: an α-helix; the pg1 pseudogtpase domain

Full ARHGAP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP5 p.Arg1193Cys Uncertain significance ★★ ⚠ same type
ARHGAP5 p.Asn953Ser Benign ★★ same type
ARHGAP5 p.Asp971= Benign ★★ same type
ARHGAP5 p.Gln726= Benign ★★ same type
ARHGAP5 p.Leu342= Benign ★★ same type
ARHGAP5 p.Pro768= Benign ★★ same type
ARHGAP5 p.Val418= Benign ★★ same type
ARHGAP5 p.Ala1064Val 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/arhgap5-p-ser683phe (accessed [today's date]).

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