Is KLC3 p.Arg451Pro (c.1352G>C) pathogenic?

KLC3 p.Arg451Pro (c.1352G>C) is classified Uncertain significance in KLC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-09). AlphaMissense: ambiguous (0.4434); Very rare (popmax 0.00534%, afr).

How common is KLC3 p.Arg451Pro (c.1352G>C) in the general population?

KLC3 p.Arg451Pro (c.1352G>C) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about KLC3 p.Arg451Pro (c.1352G>C)?

AlphaMissense predicts ambiguous (score 0.4434) — an in-silico prediction, not a clinical call.

KLC3 p.Arg451Pro

c.1352G>C · rs199586485 · VCV3115224

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4434 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.4434	ambiguous
REVEL	0.576	indeterminate
SaProt	LLR -10.40	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 8.4	GERP 1.5, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 5,812 bp · p 2.8e-09 · regional, not allelic
Overall
CADD	26.5	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 0.00534% African / African-American · 4/74,860 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000434% 7/1,612,974 alleles · very rare exomes 1/1,460,898 · genomes 6/152,076 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,715
Remaining individualsnot grpmax-eligible	0.0032%	31,218
Admixed American	0.00167%	59,806

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: KLC3
Protein: p.Arg451Pro
Coding: c.1352G>C
MANE Select: NM_177417
dbSNP: rs199586485
Type: single nucleotide variant
Location: chr19:45350720 (GRCh38)

Full KLC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/klc3-p-arg451pro (accessed [today's date]).

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