Is PKLR p.Ala92Asp (c.275C>A) pathogenic?

PKLR p.Ala92Asp (c.275C>A) is classified Uncertain significance in PKLR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-18). AlphaMissense: likely pathogenic (0.9861); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PKLR p.Ala92Asp (c.275C>A)?

PKLR p.Ala92Asp (c.275C>A) is associated with Inborn genetic diseases (ClinVar).

How common is PKLR p.Ala92Asp (c.275C>A) in the general population?

PKLR p.Ala92Asp (c.275C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PKLR p.Ala92Asp (c.275C>A)?

AlphaMissense predicts likely pathogenic (score 0.9861) — an in-silico prediction, not a clinical call.

PKLR p.Ala92Asp

c.275C>A · rs2525336892 · VCV2233957

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9861 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9861	likely pathogenic · top 6% in PKLR
REVEL	0.89	moderately pathogenic-leaning
SaProt	LLR -8.76	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -2.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,868 bp · p 0.44 · regional, not allelic
Overall
CADD	27.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PKLR
Protein: p.Ala92Asp
Coding: c.275C>A
MANE Select: NM_000298
dbSNP: rs2525336892
Type: single nucleotide variant
Location: chr1:155300106 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 67 PDB
Residue 92: a β-strand

Full PKLR 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

PKLR p.Ala92Pro Uncertain significance ★ ⚠ same residue
PKLR p.Arg488Ter Pathogenic ★★ same condition
PKLR p.Arg13Gln Uncertain significance ★★ ⚠ same condition
PKLR p.Arg435Gln Uncertain significance ★★ ⚠ same condition
PKLR p.Gln49His Uncertain significance ★★ ⚠ same condition
PKLR p.Glu241Val Uncertain significance ★★ ⚠ same condition
PKLR p.Gly169Trp Uncertain significance ★★ ⚠ same condition
PKLR p.Gly170Ser 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/pklr-p-ala92asp (accessed [today's date]).

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