Is ACTRT1 p.Met183fs (c.547dup) pathogenic?

ACTRT1 p.Met183fs (c.547dup) is classified Conflicting classifications of pathogenicity in ACTRT1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2023-09-01). Rare (popmax 0.303%, nfe); Associated with Male infertility with azoospermia or oligozoospermia due to single gene mutation.

What condition is associated with ACTRT1 p.Met183fs (c.547dup)?

ACTRT1 p.Met183fs (c.547dup) is associated with Male infertility with azoospermia or oligozoospermia due to single gene mutation (ClinVar).

How common is ACTRT1 p.Met183fs (c.547dup) in the general population?

ACTRT1 p.Met183fs (c.547dup) is rare (popmax 0.303%, nfe) (gnomAD).

ACTRT1 p.Met183fs

c.547dup · rs771087307 · VCV1205854

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.303%, nfe)

Conditions

Male infertility with azoospermia or oligozoospermia due to single gene mutation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (1 of 1) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.4	phastCons 0.93
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.303% European (non-Finnish) · 2,714/895,012 alleles

Filtering AF 0.294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.29%

Overall 0.257% 3,103/1,209,212 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.554%	180
European (non-Finnish)grpmax	0.303%	330
Remaining individualsnot grpmax-eligible	0.193%	517
Admixed American	0.0438%	2,283
African / African-American	0.0263%	3,802
Middle Eastern	0.0231%	4,337
Ashkenazi Jewishnot grpmax-eligible	0.0136%	7,343

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ACTRT1
Protein: p.Met183fs
Coding: c.547dup
MANE Select: NM_138289
dbSNP: rs771087307
Type: Duplication
Location: chrX:128051659 (GRCh38)
Structure: AlphaFold pLDDT 92.94

Full ACTRT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Male infertility with azoospermia or oligozoospermia due to single gene mutation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/actrt1-p-met183fs (accessed [today's date]).

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