Is PGK2 p.Ser415Cys (c.1243A>T) pathogenic?

PGK2 p.Ser415Cys (c.1243A>T) is classified Uncertain significance in PGK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: ambiguous (0.3441); Ultra-rare (popmax 0.0147%, afr).

How common is PGK2 p.Ser415Cys (c.1243A>T) in the general population?

PGK2 p.Ser415Cys (c.1243A>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about PGK2 p.Ser415Cys (c.1243A>T)?

AlphaMissense predicts ambiguous (score 0.3441) — an in-silico prediction, not a clinical call.

PGK2 p.Ser415Cys

c.1243A>T · rs767034775 · VCV3211799

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3441 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3441	ambiguous
REVEL	0.647	pathogenic-leaning
SaProt	LLR -11.02	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense 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 2, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 1,250 bp · p 0.00031 · regional, not allelic
Overall
CADD	24.5	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 0.0147% African / African-American · 11/74,932 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.000806% 13/1,613,694 alleles · ultra-rare exomes 5/1,461,498 · genomes 8/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,812
Admixed American	0.00167%	59,970
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: PGK2
Protein: p.Ser415Cys
Coding: c.1243A>T
MANE Select: NM_138733
dbSNP: rs767034775
Type: single nucleotide variant
Location: chr6:49785945 (GRCh38)
Gene constraint: LOEUF 1.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.34

Full PGK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PGK2 p.Ala102Thr Uncertain significance ★ ⚠ same type
PGK2 p.Ala109Asp Uncertain significance ★ ⚠ same type
PGK2 p.Ala172Thr Uncertain significance ★ ⚠ same type
PGK2 p.Ala210Ser Uncertain significance ★ ⚠ same type
PGK2 p.Ala55Gly Uncertain significance ★ ⚠ same type
PGK2 p.Ala55Ser Uncertain significance ★ ⚠ same type
PGK2 p.Arg171Cys Uncertain significance ★ ⚠ same type
PGK2 p.Arg171His 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/pgk2-p-ser415cys (accessed [today's date]).

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