Is ACTMAP p.Thr165Met (c.494C>T) pathogenic?

ACTMAP p.Thr165Met (c.494C>T) is classified Uncertain significance in ACTMAP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). AlphaMissense: likely pathogenic (0.6905); Ultra-rare (popmax 0.028%, afr).

How common is ACTMAP p.Thr165Met (c.494C>T) in the general population?

ACTMAP p.Thr165Met (c.494C>T) is ultra-rare (popmax 0.028%, afr) (gnomAD).

What do computational predictors say about ACTMAP p.Thr165Met (c.494C>T)?

AlphaMissense predicts likely pathogenic (score 0.6905) — an in-silico prediction, not a clinical call.

ACTMAP p.Thr165Met

c.494C>T · rs376159169 · VCV3141718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6905 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6905	likely pathogenic
REVEL	0.573	indeterminate
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,367 bp · p 0.5 · regional, not allelic
Overall
CADD	29.5	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 0.028% African / African-American · 21/74,932 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00421% 68/1,613,600 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,568
European (non-Finnish)	0.00373%	26,816
Admixed American	0.00167%	59,992
Remaining individualsnot grpmax-eligible	0.0016%	62,444
South Asian	0.0011%	91,070

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: ACTMAP
Protein: p.Thr165Met
Coding: c.494C>T
MANE Select: NM_198476
dbSNP: rs376159169
Type: single nucleotide variant
Location: chr19:40744582 (GRCh38)
Structure: AlphaFold pLDDT 83.63
Residue 165: the 'peptidase c39-like' region

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

Similar variants

ACTMAP p.Ala63Thr Uncertain significance ★ ⚠ same type
ACTMAP p.Arg157Trp Uncertain significance ★ ⚠ same type
ACTMAP p.Arg334Trp Uncertain significance ★ ⚠ same type
ACTMAP p.Pro151Ser Uncertain significance ★ ⚠ same type
ACTMAP p.Val327Met 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/actmap-p-thr165met (accessed [today's date]).

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