Is ACAP1 p.Arg488Cys (c.1462C>T) pathogenic?

ACAP1 p.Arg488Cys (c.1462C>T) is classified Uncertain significance in ACAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-04). AlphaMissense: ambiguous (0.4792); Ultra-rare (popmax 0.0275%, sas).

How common is ACAP1 p.Arg488Cys (c.1462C>T) in the general population?

ACAP1 p.Arg488Cys (c.1462C>T) is ultra-rare (popmax 0.0275%, sas) (gnomAD).

What do computational predictors say about ACAP1 p.Arg488Cys (c.1462C>T)?

AlphaMissense predicts ambiguous (score 0.4792) — an in-silico prediction, not a clinical call.

ACAP1 p.Arg488Cys

c.1462C>T · VCV4214630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4792 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0275%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4792	ambiguous
REVEL	0.256	benign-leaning
SaProt	LLR -8.44	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 3.3	GERP -1.1, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 1,202 bp · p 9e-06 · regional, not allelic
Overall
CADD	27.6	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 0.0275% South Asian · 25/91,048 alleles

Filtering AF 0.019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0163%

Overall 0.00273% 44/1,613,858 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0275%	3,642
African / African-American	0.00668%	14,978
Remaining individualsnot grpmax-eligible	0.0064%	15,621
East Asian	0.00223%	44,880
Admixed American	0.00167%	59,998
European (non-Finnish)	0.000678%	147,494

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.Arg488Cys
Coding: c.1462C>T
MANE Select: NM_014716
Type: single nucleotide variant
Location: chr17:7348175 (GRCh38)
Gene constraint: LOEUF 0.579 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.92 · 7 PDB
Residue 488: the arf-gap domain; a turn; the 'required for interaction with gulp1' region

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

Similar variants

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ACAP1 p.Ala54Thr Uncertain significance ★ ⚠ same type
ACAP1 p.Ala58Asp Uncertain significance ★ ⚠ same type
ACAP1 p.Ala596Thr Uncertain significance ★ ⚠ same type
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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-arg488cys (accessed [today's date]).

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