Is MACO1 p.Arg385Ser (c.1155G>C) pathogenic?

MACO1 p.Arg385Ser (c.1155G>C) is classified Uncertain significance in MACO1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-03-31). AlphaMissense: likely pathogenic (0.9808); Very rare (popmax 0.00342%, amr).

How common is MACO1 p.Arg385Ser (c.1155G>C) in the general population?

MACO1 p.Arg385Ser (c.1155G>C) is very rare (popmax 0.00342%, amr) (gnomAD).

What do computational predictors say about MACO1 p.Arg385Ser (c.1155G>C)?

AlphaMissense predicts likely pathogenic (score 0.9808) — an in-silico prediction, not a clinical call.

MACO1 p.Arg385Ser

c.1155G>C · VCV3292506

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9808 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00342%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9808	likely pathogenic
REVEL	0.386	indeterminate
SaProt	LLR -6.85	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 10	GERP 1.2, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 33 kb · p 3.9e-11 · regional, not allelic
Overall
CADD	32.0	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 0.00342% Admixed American · 2/58,426 alleles

Filtering AF 0.000568% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.000933% 15/1,607,726 alleles · very rare exomes 13/1,455,536 · genomes 2/152,190 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00342%	29,213
Remaining individualsnot grpmax-eligible	0.00161%	62,156
European (non-Finnish)	0.00102%	98,158

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.Arg385Ser
Coding: c.1155G>C
MANE Select: NM_018202
Type: single nucleotide variant
Location: chr1:25484116 (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.Arg385Gly Uncertain significance ★ ⚠ same residue
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.Arg429Gln 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-arg385ser (accessed [today's date]).

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