Is PKM p.Phe76Ser (c.227T>C) pathogenic?

PKM p.Phe76Ser (c.227T>C) is classified Uncertain significance in PKM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely pathogenic (0.9954); Very rare (popmax 8.5e-05%, nfe).

How common is PKM p.Phe76Ser (c.227T>C) in the general population?

PKM p.Phe76Ser (c.227T>C) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about PKM p.Phe76Ser (c.227T>C)?

AlphaMissense predicts likely pathogenic (score 0.9954) — an in-silico prediction, not a clinical call.

PKM p.Phe76Ser

c.227T>C · VCV3933224

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9954	likely pathogenic
REVEL	0.988	strongly pathogenic-leaning
SaProt	LLR -14.69	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 19 kb · p 1.3e-14 · regional, not allelic
Overall
CADD	33.0	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 8.5e-05% European (non-Finnish) · 1/1,176,084 alleles

Overall 6.21e-05% 1/1,609,706 alleles · very rare exomes 1/1,457,424 · genomes 0/152,282 · 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: PKM
Protein: p.Phe76Ser
Coding: c.227T>C
MANE Select: NM_002654
Type: single nucleotide variant
Location: chr15:72217428 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 96.94 · 61 PDB
Residue 76: a binding site; a turn

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

Similar variants

PKM p.Ile265Val Uncertain significance ★★ ⚠ same type
PKM p.Asn146= Benign ★★ same type
PKM p.Leu203= Benign ★★ same type
PKM p.Thr143= Benign ★★ same type
PKM p.Ala419Val Uncertain significance ★ ⚠ same type
PKM p.Ala8Thr Uncertain significance ★ ⚠ same type
PKM p.Ala99Gly Uncertain significance ★ ⚠ same type
PKM p.Arg106Gln 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/pkm-p-phe76ser (accessed [today's date]).

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