Is KLC3 p.Arg231Cys (c.691C>T) pathogenic?

KLC3 p.Arg231Cys (c.691C>T) is classified Uncertain significance in KLC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-02). AlphaMissense: likely pathogenic (0.5844); Ultra-rare (popmax 0.0582%, sas).

How common is KLC3 p.Arg231Cys (c.691C>T) in the general population?

KLC3 p.Arg231Cys (c.691C>T) is ultra-rare (popmax 0.0582%, sas) (gnomAD).

What do computational predictors say about KLC3 p.Arg231Cys (c.691C>T)?

AlphaMissense predicts likely pathogenic (score 0.5844) — an in-silico prediction, not a clinical call.

KLC3 p.Arg231Cys

c.691C>T · VCV3288789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5844 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0582%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5844	likely pathogenic
REVEL	0.114	moderately benign-leaning
SaProt	LLR -13.12	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -2.8, phastCons 0.99
Regional constraint	o/e 1.23	unconstrained · MANE · 5,812 bp · p 2.8e-09 · regional, not allelic
Overall
CADD	33.0	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 0.0582% South Asian · 52/89,284 alleles

Filtering AF 0.0456% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0411%

Overall 0.00899% 144/1,602,338 alleles · ultra-rare exomes 135/1,450,140 · genomes 9/152,198 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0582%	1,717
Remaining individualsnot grpmax-eligible	0.0129%	7,753
African / African-American	0.00937%	10,671
East Asian	0.00677%	14,777
European (non-Finnish)	0.00604%	16,548
Admixed American	0.00515%	19,416

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.Arg231Cys
Coding: c.691C>T
MANE Select: NM_177417
Type: single nucleotide variant
Location: chr19:45348072 (GRCh38)
Gene constraint: LOEUF 1.617 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.05

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

Similar variants

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KLC3 p.Ala256Val Uncertain significance ★ ⚠ same type
KLC3 p.Ala289Val Uncertain significance ★ ⚠ same type
KLC3 p.Ala291Val Uncertain significance ★ ⚠ same type
KLC3 p.Ala310Val Uncertain significance ★ ⚠ same type
KLC3 p.Ala317Thr Uncertain significance ★ ⚠ 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/klc3-p-arg231cys (accessed [today's date]).

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