Is MACO1 p.Pro223Ser (c.667C>T) pathogenic?

MACO1 p.Pro223Ser (c.667C>T) is classified Uncertain significance in MACO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-15). AlphaMissense: likely benign (0.0611); Ultra-rare (popmax 0.0201%, eas).

How common is MACO1 p.Pro223Ser (c.667C>T) in the general population?

MACO1 p.Pro223Ser (c.667C>T) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about MACO1 p.Pro223Ser (c.667C>T)?

AlphaMissense predicts likely benign (score 0.0611) — an in-silico prediction, not a clinical call.

MACO1 p.Pro223Ser

c.667C>T · rs182729817 · VCV2619012

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0611 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0611	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -5.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 27 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	19.93	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0201% East Asian · 9/44,752 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00781%

Overall 0.000629% 10/1,589,200 alleles · ultra-rare exomes 8/1,437,106 · genomes 2/152,094 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,972
European (non-Finnish)	8.53e-05%	1,172,208

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.Pro223Ser
Coding: c.667C>T
MANE Select: NM_018202
dbSNP: rs182729817
Type: single nucleotide variant
Location: chr1:25458405 (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-pro223ser (accessed [today's date]).

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