Is PGAM2 p.Ile64Met (c.192C>G) pathogenic?

PGAM2 p.Ile64Met (c.192C>G) is classified Uncertain significance in PGAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: likely pathogenic (0.6128); Very rare (popmax 0.00833%, amr); Associated with Inborn genetic diseases.

What condition is associated with PGAM2 p.Ile64Met (c.192C>G)?

PGAM2 p.Ile64Met (c.192C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PGAM2 p.Ile64Met (c.192C>G) in the general population?

PGAM2 p.Ile64Met (c.192C>G) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about PGAM2 p.Ile64Met (c.192C>G)?

AlphaMissense predicts likely pathogenic (score 0.6128) — an in-silico prediction, not a clinical call.

PGAM2 p.Ile64Met

c.192C>G · rs574780045 · VCV3211625

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6128 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6128	likely pathogenic
REVEL	0.39	indeterminate
SaProt	LLR -10.30	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.3	GERP -0.47, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,762 bp · p 0.7 · regional, not allelic
Overall
CADD	21.8	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 0.00833% Admixed American · 5/60,034 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.000496% 8/1,613,824 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,007
African / African-American	0.00266%	37,529
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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: PGAM2
Protein: p.Ile64Met
Coding: c.192C>G
MANE Select: NM_001014436 · reported on NM_000290
dbSNP: rs574780045
Type: single nucleotide variant
Location: chr7:44065338 (GRCh38)

Full PGAM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/pgam2-p-ile64met (accessed [today's date]).

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