Is KLC2 p.Asp166Val (c.497A>T) pathogenic?

KLC2 p.Asp166Val (c.497A>T) is classified Uncertain significance in KLC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.612); Ultra-rare (popmax 0.0379%, eas).

How common is KLC2 p.Asp166Val (c.497A>T) in the general population?

KLC2 p.Asp166Val (c.497A>T) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

What do computational predictors say about KLC2 p.Asp166Val (c.497A>T)?

AlphaMissense predicts likely pathogenic (score 0.612) — an in-silico prediction, not a clinical call.

KLC2 p.Asp166Val

c.497A>T · rs751238282 · VCV2694428

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.612 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.612	likely pathogenic
REVEL	0.402	indeterminate
SaProt	LLR -8.20	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 8,358 bp · p 1.4e-14 · regional, not allelic
Overall
CADD	27.0	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 0.0379% East Asian · 17/44,880 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0031% 50/1,613,286 alleles · ultra-rare exomes 41/1,461,170 · genomes 9/152,116 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0384%	2,601
East Asiangrpmax	0.0379%	2,640
African / African-American	0.0107%	9,361
European (non-Finnish)	8.47e-05%	1,179,976

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: KLC2
Protein: p.Asp166Val
Coding: c.497A>T
MANE Select: NM_001318734
dbSNP: rs751238282
Type: single nucleotide variant
Location: chr11:66262160 (GRCh38)
Gene constraint: LOEUF 0.616 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.79 · 2 PDB
Residue 166: the 'disordered' region

Full KLC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KLC2 p.Asp166Asn Uncertain significance ★ ⚠ same residue
KLC2 p.Arg110His Uncertain significance ★★ ⚠ same type
KLC2 p.Arg418Gln Uncertain significance ★★ ⚠ same type
KLC2 p.Arg418Trp Uncertain significance ★★ ⚠ same type
KLC2 p.Arg479His Uncertain significance ★★ ⚠ same type
KLC2 p.Arg509Gln Uncertain significance ★★ ⚠ same type
KLC2 p.Arg616Gln Uncertain significance ★★ ⚠ same type
KLC2 p.Arg96Gln 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/klc2-p-asp166val (accessed [today's date]).

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