Is ARAP2 p.Phe543Leu (c.1627T>C) pathogenic?

ARAP2 p.Phe543Leu (c.1627T>C) is classified Uncertain significance in ARAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely pathogenic (0.9481); Very rare (popmax 0.00474%, nfe).

How common is ARAP2 p.Phe543Leu (c.1627T>C) in the general population?

ARAP2 p.Phe543Leu (c.1627T>C) is very rare (popmax 0.00474%, nfe) (gnomAD).

What do computational predictors say about ARAP2 p.Phe543Leu (c.1627T>C)?

AlphaMissense predicts likely pathogenic (score 0.9481) — an in-silico prediction, not a clinical call.

ARAP2 p.Phe543Leu

c.1627T>C · VCV3309607

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9481 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00474%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9481	likely pathogenic · top 10% in ARAP2
REVEL	0.498	indeterminate
SaProt	LLR -7.60	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 11	GERP 2.6, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 162 kb · p 0.0019 · regional, not allelic
Overall
CADD	25.0	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 0.00474% European (non-Finnish) · 54/1,138,852 alleles

Filtering AF 0.00371% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00333%

Overall 0.00363% 56/1,542,680 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00474%	21,090
Remaining individualsnot grpmax-eligible	0.00168%	59,682
African / African-American	0.00138%	72,378

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: ARAP2
Protein: p.Phe543Leu
Coding: c.1627T>C
MANE Select: NM_015230
Type: single nucleotide variant
Location: chr4:36187502 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.42 · 2 PDB
Residue 543: the ph 1 domain; a β-strand

Full ARAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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ARAP2 p.Ala1353Glu Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1375Pro Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1421Ser Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1421Thr Uncertain significance ★ ⚠ same type
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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/arap2-p-phe543leu (accessed [today's date]).

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