Is ACTL7A p.Arg40Gln (c.119G>A) pathogenic?

ACTL7A p.Arg40Gln (c.119G>A) is classified Uncertain significance in ACTL7A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: likely benign (0.089); Very rare (popmax 0.00329%, sas).

How common is ACTL7A p.Arg40Gln (c.119G>A) in the general population?

ACTL7A p.Arg40Gln (c.119G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about ACTL7A p.Arg40Gln (c.119G>A)?

AlphaMissense predicts likely benign (score 0.089) — an in-silico prediction, not a clinical call.

ACTL7A p.Arg40Gln

c.119G>A · VCV4001798

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.089 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.089	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -6.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.58	GERP 0.93, phastCons 0.9
Regional constraint	o/e 0.99	unconstrained · MANE · 1,304 bp · p 0.81 · regional, not allelic
Overall
CADD	14.46	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 0.00329% South Asian · 3/91,090 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00186% 30/1,614,084 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,363
East Asian	0.00223%	44,846
European (non-Finnish)	0.00203%	49,168
Remaining individualsnot grpmax-eligible	0.0016%	62,506
African / African-American	0.00133%	75,038

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.Arg40Gln
Coding: c.119G>A
MANE Select: NM_006687
Type: single nucleotide variant
Location: chr9:108862441 (GRCh38)
Gene constraint: LOEUF 1.182 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.81 · 1 PDB
Residue 40: the 'disordered' region; the 'required for interaction with tes' region

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.Ala190Asp 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

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-arg40gln (accessed [today's date]).

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