Is ACTL7A p.Ala190Asp (c.569C>A) pathogenic?

ACTL7A p.Ala190Asp (c.569C>A) is classified Uncertain significance in ACTL7A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-11). AlphaMissense: likely benign (0.2034); Rare (popmax 0.111%, afr).

How common is ACTL7A p.Ala190Asp (c.569C>A) in the general population?

ACTL7A p.Ala190Asp (c.569C>A) is rare (popmax 0.111%, afr) (gnomAD).

What do computational predictors say about ACTL7A p.Ala190Asp (c.569C>A)?

AlphaMissense predicts likely benign (score 0.2034) — an in-silico prediction, not a clinical call.

ACTL7A p.Ala190Asp

c.569C>A · rs370929490 · VCV2347476

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2034 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.111%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2034	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -7.86	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 1.2	GERP -1.2, phastCons 0.93
Regional constraint	o/e 0.99	unconstrained · MANE · 1,304 bp · p 0.81 · regional, not allelic
Overall
CADD	20.5	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 0.111% African / African-American · 83/75,026 alleles

Filtering AF 0.0914% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0843%

Overall 0.00726% 117/1,612,032 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.111%	904
Middle Eastern	0.0165%	6,060
Admixed American	0.015%	6,660
Remaining individualsnot grpmax-eligible	0.0128%	7,802
European (non-Finnish)	0.00127%	78,591
South Asian	0.0011%	90,650

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: ACTL7A
Protein: p.Ala190Asp
Coding: c.569C>A
MANE Select: NM_006687
dbSNP: rs370929490
Type: single nucleotide variant
Location: chr9:108862891 (GRCh38)
Gene constraint: LOEUF 1.182 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.81 · 1 PDB
Residue 190: a UniProt-annotated variant site (in spgf86; likely pathogenic); a UniProt-annotated variant site (in spgf86; likely pathogenic; loss of protein expression in patient sperm)

Full ACTL7A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTL7A p.Arg373His Likely pathogenic ★ same type
ACTL7A p.Gly402Ser Likely pathogenic ★ same type
ACTL7A p.Ala166Glu Uncertain significance ★ ⚠ same type
ACTL7A p.Ala166Val Uncertain significance ★ ⚠ same type
ACTL7A p.Ala27Asp Uncertain significance ★ ⚠ same type
ACTL7A p.Ala86Gly Uncertain significance ★ ⚠ same type
ACTL7A p.Arg113Cys Uncertain significance ★ ⚠ same type
ACTL7A p.Arg113His 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/actl7a-p-ala190asp (accessed [today's date]).

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