Is ACTL7B p.Leu362Phe (c.1084C>T) pathogenic?

ACTL7B p.Leu362Phe (c.1084C>T) is classified Uncertain significance in ACTL7B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-07). AlphaMissense: likely benign (0.1198); Ultra-rare (popmax 0.0136%, afr).

How common is ACTL7B p.Leu362Phe (c.1084C>T) in the general population?

ACTL7B p.Leu362Phe (c.1084C>T) is ultra-rare (popmax 0.0136%, afr) (gnomAD).

What do computational predictors say about ACTL7B p.Leu362Phe (c.1084C>T)?

AlphaMissense predicts likely benign (score 0.1198) — an in-silico prediction, not a clinical call.

ACTL7B p.Leu362Phe

c.1084C>T · VCV3483873

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1198 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1198	likely benign
REVEL	0.567	indeterminate
SaProt	LLR -10.02	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.007, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,244 bp · p 0.29 · regional, not allelic
Overall
CADD	24.7	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 0.0136% African / African-American · 10/73,798 alleles

Filtering AF 0.00733% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00557%

Overall 0.000696% 11/1,579,430 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0136%	7,380
European (non-Finnish)	8.61e-05%	1,161,935

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: ACTL7B
Protein: p.Leu362Phe
Coding: c.1084C>T
MANE Select: NM_006686
Type: single nucleotide variant
Location: chr9:108854847 (GRCh38)
Gene constraint: LOEUF 1.414 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.35

Full ACTL7B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACTL7B p.Ala263= Benign ★★ same type
ACTL7B p.Ala164Thr Uncertain significance ★ ⚠ same type
ACTL7B p.Ala240Val Uncertain significance ★ ⚠ same type
ACTL7B p.Ala243Thr Uncertain significance ★ ⚠ same type
ACTL7B p.Ala28Val Uncertain significance ★ ⚠ same type
ACTL7B p.Ala2Val Uncertain significance ★ ⚠ same type
ACTL7B p.Ala36Gly Uncertain significance ★ ⚠ same type
ACTL7B p.Ala388Ser 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/actl7b-p-leu362phe (accessed [today's date]).

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