Is ACAP1 p.Leu666Val (c.1996C>G) pathogenic?

ACAP1 p.Leu666Val (c.1996C>G) is classified Uncertain significance in ACAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: likely benign (0.0937); Ultra-rare (popmax 0.0209%, nfe).

How common is ACAP1 p.Leu666Val (c.1996C>G) in the general population?

ACAP1 p.Leu666Val (c.1996C>G) is ultra-rare (popmax 0.0209%, nfe) (gnomAD).

What do computational predictors say about ACAP1 p.Leu666Val (c.1996C>G)?

AlphaMissense predicts likely benign (score 0.0937) — an in-silico prediction, not a clinical call.

ACAP1 p.Leu666Val

c.1996C>G · VCV3470326

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0937 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0937	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -5.94	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 0.013	GERP -2.3, phastCons 0.001
Regional constraint	o/e 0.63	unconstrained · MANE · 2,360 bp · p 4.1e-08 · regional, not allelic
Overall
CADD	13.59	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0209% European (non-Finnish) · 247/1,180,038 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0179%

Overall 0.0169% 272/1,614,226 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0209%	4,777
Admixed American	0.02%	5,002
Finnishnot grpmax-eligible	0.00625%	16,012
South Asian	0.00439%	22,773
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0032%	31,255
African / African-American	0.00266%	37,527

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.Leu666Val
Coding: c.1996C>G
MANE Select: NM_014716
Type: single nucleotide variant
Location: chr17:7350161 (GRCh38)
Gene constraint: LOEUF 0.579 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.92 · 7 PDB
Residue 666: 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-leu666val (accessed [today's date]).

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