Is PKLR p.Arg40Trp (c.118C>T) pathogenic?

PKLR p.Arg40Trp (c.118C>T) is classified Uncertain significance in PKLR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-17). AlphaMissense: likely benign (0.1515); Very rare (popmax 0.0035%, amr).

How common is PKLR p.Arg40Trp (c.118C>T) in the general population?

PKLR p.Arg40Trp (c.118C>T) is very rare (popmax 0.0035%, amr) (gnomAD).

What do computational predictors say about PKLR p.Arg40Trp (c.118C>T)?

AlphaMissense predicts likely benign (score 0.1515) — an in-silico prediction, not a clinical call.

PKLR p.Arg40Trp

c.118C>T · VCV3379933

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1515 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0035%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1515	likely benign
REVEL	0.584	indeterminate
SaProt	LLR -11.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -3, phastCons 0.058
Regional constraint	o/e 0.97	unconstrained · MANE · 7,868 bp · p 0.44 · regional, not allelic
Overall
CADD	22.8	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 0.0035% Admixed American · 2/57,106 alleles

Filtering AF 0.00173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0015%

Overall 0.00225% 36/1,599,290 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00485%	20,628
Admixed Americangrpmax	0.0035%	28,553
European (non-Finnish)	0.00247%	40,459
East Asian	0.00227%	44,000
South Asian	0.00111%	89,704

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.Arg40Trp
Coding: c.118C>T
MANE Select: NM_000298
Type: single nucleotide variant
Location: chr1:155300263 (GRCh38)
Gene constraint: LOEUF 0.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.75 · 67 PDB
Residue 40: a UniProt-annotated variant site (in cnsha2)

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

Similar variants

PKLR p.Arg40Gln Uncertain significance ★★ ⚠ same residue
PKLR c.101-1G>A Pathogenic ★★ same type
PKLR c.1116+2T>G Pathogenic ★★ same type
PKLR c.1618+1G>A Likely pathogenic ★★ same type
PKLR c.694+2T>G Pathogenic/Likely pathogenic ★★ same type
PKLR p.Ala423= Pathogenic/Likely pathogenic ★★ same type
PKLR p.Ala495Thr Likely pathogenic ★★ ⚠ same type
PKLR p.Ala495Val 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/pklr-p-arg40trp (accessed [today's date]).

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