Is PMM2 p.Pro69Ala (c.205C>G) pathogenic?

PMM2 p.Pro69Ala (c.205C>G) is classified Uncertain significance in PMM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-19). AlphaMissense: likely benign (0.1184); Very rare (popmax 0.00133%, afr).

How common is PMM2 p.Pro69Ala (c.205C>G) in the general population?

PMM2 p.Pro69Ala (c.205C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PMM2 p.Pro69Ala (c.205C>G)?

AlphaMissense predicts likely benign (score 0.1184) — an in-silico prediction, not a clinical call.

PMM2 p.Pro69Ala

c.205C>G · rs769648248 · VCV3251840

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1184 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1184	likely benign
REVEL	0.404	indeterminate
SaProt	LLR -6.09	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 1.1, phastCons 1
Regional constraint	o/e 1.26	unconstrained · MANE · 50 kb · p 4.8e-06 · regional, not allelic
Overall
CADD	17.84	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 0.00133% African / African-American · 1/74,976 alleles

Overall 6.2e-05% 1/1,613,230 alleles · very rare exomes 1/1,461,056 · genomes 0/152,174 · 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: PMM2
Protein: p.Pro69Ala
Coding: c.205C>G
MANE Select: NM_000303
dbSNP: rs769648248
Type: single nucleotide variant
Location: chr16:8804793 (GRCh38)
Gene constraint: LOEUF 1.937 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.66 · 7 PDB
Residue 69: a UniProt-annotated variant site (in cdg1a); an α-helix

Full PMM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PMM2 p.Pro69Ser Pathogenic/Likely pathogenic ★★ ⚠ same residue
PMM2 p.Pro69Leu Likely pathogenic ★ same residue
PMM2 p.Pro69Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
PMM2 p.Pro69= Likely benign ★ same residue
PMM2 c.178+1G>A Likely pathogenic ★★ same type
PMM2 c.178+2T>G Likely pathogenic ★★ same type
PMM2 c.179-1G>C Pathogenic/Likely pathogenic ★★ same type
PMM2 c.179-25A>G Likely 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/pmm2-p-pro69ala (accessed [today's date]).

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