Is PKLR p.Ala495Val (c.1484C>T) pathogenic?

PKLR p.Ala495Val (c.1484C>T) is classified Pathogenic in PKLR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-04). AlphaMissense: likely benign (0.3188); Ultra-rare (popmax 0.0113%, nfe); Associated with PKLR-related disorder.

What condition is associated with PKLR p.Ala495Val (c.1484C>T)?

PKLR p.Ala495Val (c.1484C>T) is associated with PKLR-related disorder (ClinVar).

How common is PKLR p.Ala495Val (c.1484C>T) in the general population?

PKLR p.Ala495Val (c.1484C>T) is ultra-rare (popmax 0.0113%, nfe) (gnomAD).

What do computational predictors say about PKLR p.Ala495Val (c.1484C>T)?

AlphaMissense predicts likely benign (score 0.3188) — an in-silico prediction, not a clinical call.

PKLR p.Ala495Val

c.1484C>T · rs141560532 · VCV2063906

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.3188 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PKLR-related disorder

Computational evidence

Protein change
AlphaMissense	0.3188	likely benign ⚠ discordant with ClinVar
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -8.69	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 2,951 bp · p 2.2e-05 · regional, not allelic
Overall
CADD	27.4	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 0.0113% European (non-Finnish) · 133/1,180,018 alleles

Filtering AF 0.00969% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00936% 151/1,613,820 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0272%	3,673
European (non-Finnish)grpmax	0.0113%	8,872
African / African-American	0.00133%	74,930

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: PKLR
Protein: p.Ala495Val
Coding: c.1484C>T
MANE Select: NM_000298
dbSNP: rs141560532
Type: single nucleotide variant
Location: chr1:155291890 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 67 PDB
Residue 495: a UniProt-annotated variant site (in cnsha2); a β-strand

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

Disease context

PKLR-related disorder

Similar variants

PKLR p.Ala495Thr Likely pathogenic ★★ ⚠ same residue
PKLR c.1116+2T>G Pathogenic ★★ same condition
PKLR p.Arg479His Pathogenic ★★ ⚠ same condition
PKLR p.Arg486Trp Pathogenic/Likely pathogenic ★★ same condition
PKLR p.Arg510Gln Pathogenic ★★ ⚠ same condition
PKLR p.Arg510Ter Pathogenic ★★ same condition
PKLR p.Arg532Trp Pathogenic/Likely pathogenic ★★ same condition
PKLR p.Asn393Lys 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/pklr-p-ala495val (accessed [today's date]).

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