Is ARHGAP39 p.Phe796Leu (c.2388C>G) pathogenic?

ARHGAP39 p.Phe796Leu (c.2388C>G) is classified Uncertain significance in ARHGAP39 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely pathogenic (0.9656); Ultra-rare (popmax 0.0168%, amr).

How common is ARHGAP39 p.Phe796Leu (c.2388C>G) in the general population?

ARHGAP39 p.Phe796Leu (c.2388C>G) is ultra-rare (popmax 0.0168%, amr) (gnomAD).

What do computational predictors say about ARHGAP39 p.Phe796Leu (c.2388C>G)?

AlphaMissense predicts likely pathogenic (score 0.9656) — an in-silico prediction, not a clinical call.

ARHGAP39 p.Phe796Leu

c.2388C>G · VCV4136959

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9656 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9656	likely pathogenic
REVEL	0.42	indeterminate
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.98, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 15 kb · p 4e-08 · regional, not allelic
Overall
CADD	22.3	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 0.0168% Admixed American · 10/59,658 alleles

Filtering AF 0.00905% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00685%

Overall 0.00138% 22/1,598,968 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0168%	5,966
Remaining individualsnot grpmax-eligible	0.00162%	61,896
European (non-Finnish)	0.000939%	106,528

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: ARHGAP39
Protein: p.Phe796Leu
Coding: c.2388C>G
MANE Select: NM_025251
Type: single nucleotide variant
Location: chr8:144545382 (GRCh38)
Gene constraint: LOEUF 0.658 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.42
Residue 796: the myth4 domain

Full ARHGAP39 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP39 p.Arg933Cys Uncertain significance ★★ ⚠ same type
ARHGAP39 p.Ala227= Benign ★★ same type
ARHGAP39 p.Thr818= Benign ★★ same type
ARHGAP39 p.Ala1033Val Uncertain significance ★ ⚠ same type
ARHGAP39 p.Ala1056Val Uncertain significance ★ ⚠ same type
ARHGAP39 p.Ala120Val Uncertain significance ★ ⚠ same type
ARHGAP39 p.Ala322Asp Uncertain significance ★ ⚠ same type
ARHGAP39 p.Ala322Thr 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/arhgap39-p-phe796leu (accessed [today's date]).

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