Is ARAP1 p.Val460Met (c.1378G>A) pathogenic?

ARAP1 p.Val460Met (c.1378G>A) is classified Uncertain significance in ARAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: ambiguous (0.3868); Ultra-rare (popmax 0.0213%, afr).

How common is ARAP1 p.Val460Met (c.1378G>A) in the general population?

ARAP1 p.Val460Met (c.1378G>A) is ultra-rare (popmax 0.0213%, afr) (gnomAD).

What do computational predictors say about ARAP1 p.Val460Met (c.1378G>A)?

AlphaMissense predicts ambiguous (score 0.3868) — an in-silico prediction, not a clinical call.

ARAP1 p.Val460Met

c.1378G>A · rs145451210 · VCV3128192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3868 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0213%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3868	ambiguous
REVEL	0.156	moderately benign-leaning
SaProt	LLR -11.07	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 15 kb · p 7.9e-09 · regional, not allelic
Overall
CADD	26.3	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 0.0213% African / African-American · 16/75,008 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00328% 53/1,614,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0213%	4,688
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0064%	15,627
European (non-Finnish)	0.00263%	38,064
Admixed American	0.00167%	60,012

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.Val460Met
Coding: c.1378G>A
MANE Select: NM_001040118
dbSNP: rs145451210
Type: single nucleotide variant
Location: chr11:72710423 (GRCh38)
Gene constraint: LOEUF 0.572 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 1 PDB
Residue 460: the ph 2 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-val460met (accessed [today's date]).

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