Is MMUT p.Pro424Ser (c.1270C>T) pathogenic?

MMUT p.Pro424Ser (c.1270C>T) is classified Uncertain significance in MMUT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-15). AlphaMissense: likely pathogenic (0.8749); Very rare (popmax 0.00401%, afr).

How common is MMUT p.Pro424Ser (c.1270C>T) in the general population?

MMUT p.Pro424Ser (c.1270C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about MMUT p.Pro424Ser (c.1270C>T)?

AlphaMissense predicts likely pathogenic (score 0.8749) — an in-silico prediction, not a clinical call.

MMUT p.Pro424Ser

c.1270C>T · rs373381232 · VCV1433445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8749	likely pathogenic
REVEL	0.975	strongly pathogenic-leaning
SaProt	LLR -13.00	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 28 kb · p 0.059 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00401% African / African-American · 3/74,892 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,872 alleles · very rare exomes 0/1,461,766 · genomes 3/152,106 · joint denominator

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: MMUT
Protein: p.Pro424Ser
Coding: c.1270C>T
MANE Select: NM_000255
dbSNP: rs373381232
Type: single nucleotide variant
Location: chr6:49451528 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.72 · 6 PDB
Residue 424: a UniProt-annotated variant site (in mamm; mut0; decreased protein abundance; decreased methylmalonyl-coa mutase activity); a UniProt-annotated variant site (in mamm; mut-); a turn; a UniProt-annotated variant site (in mamm; mut0)

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

Similar variants

MMUT p.Pro424Leu Pathogenic ★★ same residue
MMUT p.Pro424= Likely benign ★ same residue
MMUT c.1083+2T>A Pathogenic ★★ same type
MMUT c.1084-10A>G Pathogenic/Likely pathogenic ★★ same type
MMUT c.1084-2A>G Pathogenic/Likely pathogenic ★★ same type
MMUT c.1445-2A>G Pathogenic/Likely pathogenic ★★ same type
MMUT c.1560+1G>T Pathogenic ★★ same type
MMUT c.1677-1G>A Pathogenic ★★ 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/mmut-p-pro424ser (accessed [today's date]).

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