Is ARHGEF35 p.Pro154Ser (c.460C>T) pathogenic?

ARHGEF35 p.Pro154Ser (c.460C>T) is classified Uncertain significance in ARHGEF35 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). AlphaMissense: likely benign (0.257); Very rare (popmax 0.00108%, nfe).

How common is ARHGEF35 p.Pro154Ser (c.460C>T) in the general population?

ARHGEF35 p.Pro154Ser (c.460C>T) is very rare (popmax 0.00108%, nfe) (gnomAD).

What do computational predictors say about ARHGEF35 p.Pro154Ser (c.460C>T)?

AlphaMissense predicts likely benign (score 0.257) — an in-silico prediction, not a clinical call.

ARHGEF35 p.Pro154Ser

c.460C>T · VCV3427608

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.257 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00108%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.257	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -5.82	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 2	GERP 0.43, phastCons 0.31
Regional constraint	o/e 0.01	constrained · MANE · 996 bp · p 2e-58 · regional, not allelic
Overall
CADD	16.23	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 0.00108% European (non-Finnish) · 8/743,168 alleles

Filtering AF 0.000463% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000335%

Overall 0.000786% 8/1,018,268 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: ARHGEF35
Protein: p.Pro154Ser
Coding: c.460C>T
MANE Select: NM_001003702
Type: single nucleotide variant
Location: chr7:144187924 (GRCh38)
Gene constraint: LOEUF 1.886 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 44.69
Residue 154: the 'disordered' region

Full ARHGEF35 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGEF35 p.Ala126Thr Uncertain significance ★ ⚠ same type
ARHGEF35 p.Ala199Thr Uncertain significance ★ ⚠ same type
ARHGEF35 p.Ala447Thr Uncertain significance ★ ⚠ same type
ARHGEF35 p.Ala448Thr Uncertain significance ★ ⚠ same type
ARHGEF35 p.Arg286Thr Uncertain significance ★ ⚠ same type
ARHGEF35 p.Arg290Thr Uncertain significance ★ ⚠ same type
ARHGEF35 p.Arg328Met Uncertain significance ★ ⚠ same type
ARHGEF35 p.Arg392Ser 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/arhgef35-p-pro154ser (accessed [today's date]).

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