Is ARAP1 p.Val974Leu (c.2920G>C) pathogenic?

ARAP1 p.Val974Leu (c.2920G>C) is classified Uncertain significance in ARAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-09). AlphaMissense: ambiguous (0.4672); Ultra-rare (popmax 0.0901%, amr).

How common is ARAP1 p.Val974Leu (c.2920G>C) in the general population?

ARAP1 p.Val974Leu (c.2920G>C) is ultra-rare (popmax 0.0901%, amr) (gnomAD).

What do computational predictors say about ARAP1 p.Val974Leu (c.2920G>C)?

AlphaMissense predicts ambiguous (score 0.4672) — an in-silico prediction, not a clinical call.

ARAP1 p.Val974Leu

c.2920G>C · rs138209865 · VCV2368593

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4672 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0901%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4672	ambiguous
REVEL	0.25	benign-leaning
SaProt	LLR -8.55	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 4.6	GERP 2.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,408 bp · p 0.49 · regional, not allelic
Overall
CADD	24.2	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 0.0901% Admixed American · 52/57,690 alleles

Filtering AF 0.0705% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0635%

Overall 0.0377% 604/1,601,710 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0901%	1,109
European (non-Finnish)	0.0445%	2,246
Remaining individualsnot grpmax-eligible	0.0274%	3,646
African / African-American	0.0134%	7,490
Ashkenazi Jewishnot grpmax-eligible	0.00342%	29,268
South Asian	0.00111%	89,694

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: ARAP1
Protein: p.Val974Leu
Coding: c.2920G>C
MANE Select: NM_001040118
dbSNP: rs138209865
Type: single nucleotide variant
Location: chr11:72697356 (GRCh38)
Gene constraint: LOEUF 0.572 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 1 PDB
Residue 974: the rho-gap domain

Full ARAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARAP1 p.Gln1047Glu Benign ★★ same type
ARAP1 p.Pro1039= Benign ★★ same type
ARAP1 p.Pro254Leu Benign ★★ same type
ARAP1 p.Val1408Met Benign ★★ ⚠ same type
ARAP1 p.Ala1046Ser Uncertain significance ★ ⚠ same type
ARAP1 p.Ala1124Thr Uncertain significance ★ ⚠ same type
ARAP1 p.Ala1199Thr Uncertain significance ★ ⚠ same type
ARAP1 p.Ala1389Thr 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/arap1-p-val974leu (accessed [today's date]).

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