Is PKM p.Ser249Phe (c.746C>T) pathogenic?

PKM p.Ser249Phe (c.746C>T) is classified Uncertain significance in PKM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-29). AlphaMissense: likely pathogenic (0.6094); Very rare (popmax 0.00169%, nfe).

How common is PKM p.Ser249Phe (c.746C>T) in the general population?

PKM p.Ser249Phe (c.746C>T) is very rare (popmax 0.00169%, nfe) (gnomAD).

What do computational predictors say about PKM p.Ser249Phe (c.746C>T)?

AlphaMissense predicts likely pathogenic (score 0.6094) — an in-silico prediction, not a clinical call.

PKM p.Ser249Phe

c.746C>T · VCV4137974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6094 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6094	likely pathogenic
REVEL	0.198	benign-leaning
SaProt	LLR -15.16	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.50 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.4	GERP 1.9, phastCons 0.92
Regional constraint	o/e 0.71	unconstrained · MANE · 19 kb · p 1.3e-14 · regional, not allelic
Overall
CADD	24.4	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 0.00169% European (non-Finnish) · 20/1,179,994 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.0013% 21/1,614,124 alleles · very rare exomes 21/1,461,850 · genomes 0/152,274 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00169%	59,000
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Ser249Phe
Coding: c.746C>T
MANE Select: NM_002654
Type: single nucleotide variant
Location: chr15:72208711 (GRCh38)
Gene constraint: LOEUF 0.515 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 96.94 · 61 PDB
Residue 249: an α-helix

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-ser249phe (accessed [today's date]).

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