Is ACAP1 p.Pro540His (c.1619C>A) pathogenic?

ACAP1 p.Pro540His (c.1619C>A) is classified Uncertain significance in ACAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely benign (0.106); Very rare (popmax 0.00079%, nfe).

How common is ACAP1 p.Pro540His (c.1619C>A) in the general population?

ACAP1 p.Pro540His (c.1619C>A) is very rare (popmax 0.00079%, nfe) (gnomAD).

What do computational predictors say about ACAP1 p.Pro540His (c.1619C>A)?

AlphaMissense predicts likely benign (score 0.106) — an in-silico prediction, not a clinical call.

ACAP1 p.Pro540His

c.1619C>A · VCV4636640

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.106 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00079%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.106	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -10.19	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.24	unconstrained · MANE · 661 bp · p 0.052 · regional, not allelic
Overall
CADD	24.8	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 0.00079% European (non-Finnish) · 9/1,139,250 alleles

Filtering AF 0.000372% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000269%

Overall 0.000589% 9/1,528,008 alleles · very rare

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: ACAP1
Protein: p.Pro540His
Coding: c.1619C>A
MANE Select: NM_014716
Type: single nucleotide variant
Location: chr17:7348416 (GRCh38)
Gene constraint: LOEUF 0.579 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.92 · 7 PDB
Residue 540: the 'disordered' region; the 'prevents interaction with itgb1 when s-554 is not phosphorylated' region; the 'required for interaction with gulp1' region

Full ACAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACAP1 p.Val407Ala Uncertain significance ★★ ⚠ same type
ACAP1 p.Ala137Thr Uncertain significance ★ ⚠ same type
ACAP1 p.Ala418Asp Uncertain significance ★ ⚠ same type
ACAP1 p.Ala54Thr Uncertain significance ★ ⚠ same type
ACAP1 p.Ala58Asp Uncertain significance ★ ⚠ same type
ACAP1 p.Ala596Thr Uncertain significance ★ ⚠ same type
ACAP1 p.Ala636Glu Uncertain significance ★ ⚠ same type
ACAP1 p.Ala636Val 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/acap1-p-pro540his (accessed [today's date]).

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