Is ARAP1 p.Pro254Leu (c.761C>T) pathogenic?

ARAP1 p.Pro254Leu (c.761C>T) is classified Benign in ARAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-05-21). AlphaMissense: likely benign (0.0558); Low-frequency (popmax 2.1%, afr).

How common is ARAP1 p.Pro254Leu (c.761C>T) in the general population?

ARAP1 p.Pro254Leu (c.761C>T) is low-frequency (popmax 2.1%, afr) (gnomAD).

What do computational predictors say about ARAP1 p.Pro254Leu (c.761C>T)?

AlphaMissense predicts likely benign (score 0.0558) — an in-silico prediction, not a clinical call.

ARAP1 p.Pro254Leu

c.761C>T · rs115556004 · VCV768465

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0558 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.1%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0558	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -7.19	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 -0.94	GERP -3.7
Regional constraint	o/e 1.20	unconstrained · MANE · 14 kb · p 0.023 · regional, not allelic
Overall
CADD	0.828	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 2.1% African / African-American · 1,570/74,920 alleles

Filtering AF 2.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.97%

Overall 0.108% 1,749/1,612,636 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.1%	48
Remaining individualsnot grpmax-eligible	0.107%	933
Admixed American	0.102%	983
Middle Eastern	0.0495%	2,019
South Asian	0.033%	3,035
Finnishnot grpmax-eligible	0.00159%	62,932
European (non-Finnish)	0.00144%	69,404

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.Pro254Leu
Coding: c.761C>T
MANE Select: NM_001040118
dbSNP: rs115556004
Type: single nucleotide variant
Location: chr11:72712555 (GRCh38)
Gene constraint: LOEUF 0.572 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 1 PDB
Residue 254: the 'disordered' region

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.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
ARAP1 p.Ala1441Ser 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-pro254leu (accessed [today's date]).

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