Is MACO1 p.Val125Met (c.373G>A) pathogenic?

MACO1 p.Val125Met (c.373G>A) is classified Uncertain significance in MACO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-01). AlphaMissense: likely pathogenic (0.7415); Ultra-rare (popmax 0.015%, nfe).

How common is MACO1 p.Val125Met (c.373G>A) in the general population?

MACO1 p.Val125Met (c.373G>A) is ultra-rare (popmax 0.015%, nfe) (gnomAD).

What do computational predictors say about MACO1 p.Val125Met (c.373G>A)?

AlphaMissense predicts likely pathogenic (score 0.7415) — an in-silico prediction, not a clinical call.

MACO1 p.Val125Met

c.373G>A · rs113398522 · VCV3121903

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7415 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7415	likely pathogenic
REVEL	0.463	indeterminate
SaProt	LLR -5.46	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 27 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	29.3	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 0.015% European (non-Finnish) · 176/1,176,034 alleles

Filtering AF 0.0131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.0118% 190/1,604,622 alleles · ultra-rare exomes 180/1,452,834 · genomes 10/151,788 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.015%	6,682
Remaining individualsnot grpmax-eligible	0.0145%	6,895
Finnishnot grpmax-eligible	0.00629%	15,908
Admixed American	0.0017%	58,674

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: MACO1
Protein: p.Val125Met
Coding: c.373G>A
MANE Select: NM_018202
dbSNP: rs113398522
Type: single nucleotide variant
Location: chr1:25454282 (GRCh38)
Gene constraint: LOEUF 0.289 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.84

Full MACO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MACO1 p.Ala382Thr Uncertain significance ★ ⚠ same type
MACO1 p.Ala39Gly Uncertain significance ★ ⚠ same type
MACO1 p.Ala493Gly Uncertain significance ★ ⚠ same type
MACO1 p.Ala589Thr Uncertain significance ★ ⚠ same type
MACO1 p.Ala84Thr Uncertain significance ★ ⚠ same type
MACO1 p.Arg139Lys Uncertain significance ★ ⚠ same type
MACO1 p.Arg385Gly Uncertain significance ★ ⚠ same type
MACO1 p.Arg385Ser 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/maco1-p-val125met (accessed [today's date]).

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