Is CLC p.Val102Leu (c.304G>T) pathogenic?

CLC p.Val102Leu (c.304G>T) is classified Uncertain significance in CLC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-14). AlphaMissense: ambiguous (0.4659); Ultra-rare (popmax 0.0495%, eas).

How common is CLC p.Val102Leu (c.304G>T) in the general population?

CLC p.Val102Leu (c.304G>T) is ultra-rare (popmax 0.0495%, eas) (gnomAD).

What do computational predictors say about CLC p.Val102Leu (c.304G>T)?

AlphaMissense predicts ambiguous (score 0.4659) — an in-silico prediction, not a clinical call.

CLC p.Val102Leu

c.304G>T · rs750982874 · VCV2213666

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4659 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4659	ambiguous
REVEL	0.057	moderately benign-leaning
SaProt	LLR -8.82	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.24	acceptor gain · deltas
Pangolin	Δ0.26	loss · gain 0.09 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP -0.39	GERP -0.26
Overall
CADD	21.7	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 0.0495% East Asian · 22/44,462 alleles

Filtering AF 0.0334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0282%

Overall 0.003% 48/1,598,670 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0495%	2,021
European (non-Finnish)	0.00205%	48,759
Admixed American	0.00171%	58,514
Remaining individualsnot grpmax-eligible	0.00162%	61,752

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: CLC
Protein: p.Val102Leu
Coding: c.304G>T
MANE Select: NM_013246 · reported on NM_001828
dbSNP: rs750982874
Type: single nucleotide variant
Location: chr19:39731505 (GRCh38)
Structure: AlphaFold pLDDT 82.59 · 2 PDB
Residue 102: an α-helix

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

Similar variants

CLCF1 p.Arg102Gln Uncertain significance ★ ⚠ same residue
CLCF1 p.Arg122His Uncertain significance ★★ ⚠ same type
CLCF1 p.Arg130His Uncertain significance ★★ ⚠ same type
CLCF1 p.Arg30His Uncertain significance ★★ ⚠ same type
CLCF1 p.Pro38Ser Uncertain significance ★★ ⚠ same type
CLCF1 p.Ser198Leu Uncertain significance ★★ ⚠ same type
CLC p.Asn65Lys Benign ★★ ⚠ same type
CLCF1 c.183+14G>A Benign ★★ 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/clc-p-val102leu (accessed [today's date]).

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