Is PHKA2 p.Pro1115Ser (c.3343C>T) pathogenic?

PHKA2 p.Pro1115Ser (c.3343C>T) is classified Uncertain significance in PHKA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-22). AlphaMissense: likely benign (0.106); Ultra-rare (popmax 0.0457%, sas); Associated with disorder of glycogen metabolism.

What condition is associated with PHKA2 p.Pro1115Ser (c.3343C>T)?

PHKA2 p.Pro1115Ser (c.3343C>T) is associated with disorder of glycogen metabolism (ClinVar).

How common is PHKA2 p.Pro1115Ser (c.3343C>T) in the general population?

PHKA2 p.Pro1115Ser (c.3343C>T) is ultra-rare (popmax 0.0457%, sas) (gnomAD).

What do computational predictors say about PHKA2 p.Pro1115Ser (c.3343C>T)?

AlphaMissense predicts likely benign (score 0.106) — an in-silico prediction, not a clinical call.

PHKA2 p.Pro1115Ser

c.3343C>T · VCV4820596

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.106 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0457%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

disorder of glycogen metabolism

Computational evidence

Protein change
AlphaMissense	0.106	likely benign
REVEL	0.359	indeterminate
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 45 kb · p 0.0065 · regional, not allelic
Overall
CADD	17.06	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 0.0457% South Asian · 26/56,837 alleles

Filtering AF 0.032% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0274%

Overall 0.00215% 26/1,208,079 alleles · ultra-rare

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: PHKA2
Protein: p.Pro1115Ser
Coding: c.3343C>T
MANE Select: NM_000292
Type: single nucleotide variant
Location: chrX:18894398 (GRCh38)
Structure: AlphaFold pLDDT 81.36

Full PHKA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

disorder of glycogen metabolism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHKA2 p.Pro1115= Likely benign ★ same residue
PHKA2 p.Pro1205Leu Pathogenic/Likely pathogenic ★★ same condition
PHKA2 p.Thr1211Arg Likely pathogenic ★ same condition
PHKA2 p.Gln134Arg Uncertain significance ★ ⚠ same condition
PHKA2 p.Glu185Asp Uncertain significance ★ ⚠ same condition
PHKA2 p.Tyr116Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
PHKA2 c.1794-8_1794-6del Uncertain significance ★★ same condition
PHKA2 c.1325-2A>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/phka2-p-pro1115ser (accessed [today's date]).

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