Is PHKA2 p.Ser695Phe (c.2084C>T) pathogenic?

PHKA2 p.Ser695Phe (c.2084C>T) is classified Uncertain significance in PHKA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-03). AlphaMissense: ambiguous (0.4397); Very rare (popmax 0.00201%, nfe).

How common is PHKA2 p.Ser695Phe (c.2084C>T) in the general population?

PHKA2 p.Ser695Phe (c.2084C>T) is very rare (popmax 0.00201%, nfe) (gnomAD).

What do computational predictors say about PHKA2 p.Ser695Phe (c.2084C>T)?

AlphaMissense predicts ambiguous (score 0.4397) — an in-silico prediction, not a clinical call.

PHKA2 p.Ser695Phe

c.2084C>T · rs767559014 · VCV1696120

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4397 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00201%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4397	ambiguous
REVEL	0.558	indeterminate
SaProt	LLR -8.81	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 0.52, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 45 kb · p 0.0065 · regional, not allelic
Overall
CADD	20.3	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 0.00201% European (non-Finnish) · 18/893,846 alleles

Filtering AF 0.00126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00149% 18/1,208,760 alleles · very rare exomes 14/1,096,558 · genomes 4/112,202 · 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: PHKA2
Protein: p.Ser695Phe
Coding: c.2084C>T
MANE Select: NM_000292
dbSNP: rs767559014
Type: single nucleotide variant
Location: chrX:18918734 (GRCh38)
Structure: AlphaFold pLDDT 81.36
Residue 695: a modified residue (phosphoserine)

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

Similar variants

PHKA2 p.Ser695= Likely benign ★ same residue
PHKA2 c.1325-2A>G Likely pathogenic ★★ same type
PHKA2 c.2597+1G>A Pathogenic/Likely pathogenic ★★ same type
PHKA2 c.537+2T>C Pathogenic/Likely pathogenic ★★ same type
PHKA2 c.918+1G>A Pathogenic/Likely pathogenic ★★ same type
PHKA2 p.Arg1111Ter Pathogenic ★★ same type
PHKA2 p.Arg186Cys Pathogenic/Likely pathogenic ★★ same type
PHKA2 p.Arg186His 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-ser695phe (accessed [today's date]).

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