Is PHKA2 p.Pro329Ser (c.985C>T) pathogenic?

PHKA2 p.Pro329Ser (c.985C>T) is classified Uncertain significance in PHKA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-23). AlphaMissense: likely pathogenic (0.9343); Very rare (popmax 0.00217%, amr); Associated with Inborn genetic diseases.

What condition is associated with PHKA2 p.Pro329Ser (c.985C>T)?

PHKA2 p.Pro329Ser (c.985C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PHKA2 p.Pro329Ser (c.985C>T) in the general population?

PHKA2 p.Pro329Ser (c.985C>T) is very rare (popmax 0.00217%, amr) (gnomAD).

What do computational predictors say about PHKA2 p.Pro329Ser (c.985C>T)?

AlphaMissense predicts likely pathogenic (score 0.9343) — an in-silico prediction, not a clinical call.

PHKA2 p.Pro329Ser

c.985C>T · rs1176290982 · VCV2262219

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9343 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00217%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9343	likely pathogenic
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -12.77	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 45 kb · p 5e-08 · regional, not allelic
Overall
CADD	26.5	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 0.00217% Admixed American · 1/46,063 alleles

Filtering AF 9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000368% 4/1,085,655 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00217%	46,063
European (non-Finnish)	0.000339%	294,706

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.Pro329Ser
Coding: c.985C>T
MANE Select: NM_000292
dbSNP: rs1176290982
Type: single nucleotide variant
Location: chrX:18938683 (GRCh38)
Structure: AlphaFold pLDDT 81.36

Full PHKA2 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

Similar variants

PHKA2 p.Pro329Thr Uncertain significance ★ ⚠ same residue
PHKA2 p.Arg86Ter Pathogenic/Likely pathogenic ★★ same condition
PHKA2 p.His132Tyr Pathogenic/Likely pathogenic ★★ same condition
PHKA2 p.Ala15Val Uncertain significance ★★ ⚠ same condition
PHKA2 p.Ala257Gly Uncertain significance ★★ ⚠ same condition
PHKA2 p.Arg154Cys Uncertain significance ★★ ⚠ same condition
PHKA2 p.Arg930Gln Uncertain significance ★★ ⚠ same condition
PHKA2 p.Arg971Cys Uncertain significance ★★ ⚠ same condition

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-pro329ser (accessed [today's date]).

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