Is ACTL7A p.Pro162Leu (c.485C>T) pathogenic?

ACTL7A p.Pro162Leu (c.485C>T) is classified Uncertain significance in ACTL7A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: ambiguous (0.3473); Ultra-rare (popmax 0.0166%, mid).

How common is ACTL7A p.Pro162Leu (c.485C>T) in the general population?

ACTL7A p.Pro162Leu (c.485C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about ACTL7A p.Pro162Leu (c.485C>T)?

AlphaMissense predicts ambiguous (score 0.3473) — an in-silico prediction, not a clinical call.

ACTL7A p.Pro162Leu

c.485C>T · VCV4221235

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3473 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3473	ambiguous
REVEL	0.686	pathogenic-leaning
SaProt	LLR -10.05	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 1,304 bp · p 0.81 · regional, not allelic
Overall
CADD	24.3	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 0.0166% Middle Eastern · 1/6,042 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00204% 33/1,613,840 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,042
East Asian	0.0156%	6,412
African / African-American	0.0107%	9,363
Admixed American	0.00167%	59,994
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)	0.00119%	84,286
South Asian	0.0011%	91,072

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.Pro162Leu
Coding: c.485C>T
MANE Select: NM_006687
Type: single nucleotide variant
Location: chr9:108862807 (GRCh38)
Gene constraint: LOEUF 1.182 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.81 · 1 PDB
Residue 162: 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.Pro162Ser Uncertain significance ★ ⚠ same residue
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

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-pro162leu (accessed [today's date]).

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