Is PHKA2 p.Asp643His (c.1927G>C) pathogenic?

PHKA2 p.Asp643His (c.1927G>C) is classified Likely benign in PHKA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-08). AlphaMissense: likely benign (0.122); Very rare (popmax 0.00743%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PHKA2 p.Asp643His (c.1927G>C)?

PHKA2 p.Asp643His (c.1927G>C) is associated with Inborn genetic diseases, glycogen storage disease IXa1 (ClinVar).

How common is PHKA2 p.Asp643His (c.1927G>C) in the general population?

PHKA2 p.Asp643His (c.1927G>C) is very rare (popmax 0.00743%, nfe) (gnomAD).

What do computational predictors say about PHKA2 p.Asp643His (c.1927G>C)?

AlphaMissense predicts likely benign (score 0.122) — an in-silico prediction, not a clinical call.

PHKA2 p.Asp643His

c.1927G>C · rs369400689 · VCV1044203

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.122 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00743%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.122	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -7.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 45 kb · p 0.0065 · regional, not allelic
Overall
CADD	17.09	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 0.00743% European (non-Finnish) · 66/888,279 alleles

Filtering AF 0.00599% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00546%

Overall 0.00615% 74/1,202,479 alleles · very rare exomes 63/1,090,042 · genomes 11/112,437 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0106%	9,471
European (non-Finnish)grpmax	0.00743%	13,459
African / African-American	0.0035%	28,600
Admixed American	0.00218%	45,805

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp643His
Coding: c.1927G>C
MANE Select: NM_000292
dbSNP: rs369400689
Type: single nucleotide variant
Location: chrX:18920068 (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

Also linked: glycogen storage disease IXa1

Similar variants

PHKA2 c.1325-2A>G Likely pathogenic ★★ same condition
PHKA2 c.2597+1G>A Pathogenic/Likely pathogenic ★★ same condition
PHKA2 c.537+2T>C Pathogenic/Likely pathogenic ★★ same condition
PHKA2 c.918+1G>A Pathogenic/Likely pathogenic ★★ same condition
PHKA2 p.Arg1111Ter Pathogenic ★★ same condition
PHKA2 p.Arg186Cys Pathogenic/Likely pathogenic ★★ same condition
PHKA2 p.Arg186His Likely pathogenic ★★ same condition
PHKA2 p.Arg295Cys Pathogenic/Likely pathogenic ★★ 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-asp643his (accessed [today's date]).

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