Is KLC3 p.Ser433Phe (c.1298C>T) pathogenic?

KLC3 p.Ser433Phe (c.1298C>T) is classified Uncertain significance in KLC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). AlphaMissense: ambiguous (0.4186); Ultra-rare (popmax 0.0494%, mid).

How common is KLC3 p.Ser433Phe (c.1298C>T) in the general population?

KLC3 p.Ser433Phe (c.1298C>T) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

What do computational predictors say about KLC3 p.Ser433Phe (c.1298C>T)?

AlphaMissense predicts ambiguous (score 0.4186) — an in-silico prediction, not a clinical call.

KLC3 p.Ser433Phe

c.1298C>T · rs1040897551 · VCV2391029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4186 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

⚠ 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	0.4186	ambiguous
REVEL	0.388	indeterminate
SaProt	LLR -10.35	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Pangolin	Δ0.21	gain · loss 0.00 · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 0.24, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 5,812 bp · p 2.8e-09 · regional, not allelic
Overall
CADD	25.3	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 0.0494% Middle Eastern · 3/6,072 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00717%

Overall 0.00217% 35/1,613,742 alleles · ultra-rare exomes 34/1,461,602 · genomes 1/152,140 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,024
Remaining individualsnot grpmax-eligible	0.0064%	15,618
European (non-Finnish)	0.0022%	45,382
South Asian	0.0022%	45,522

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.Ser433Phe
Coding: c.1298C>T
MANE Select: NM_177417
dbSNP: rs1040897551
Type: single nucleotide variant
Location: chr19:45350666 (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-ser433phe (accessed [today's date]).

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