Is CLC p.Leu91Pro (c.272T>C) pathogenic?

CLC p.Leu91Pro (c.272T>C) is classified Uncertain significance in CLC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-14). AlphaMissense: likely pathogenic (0.788); Absent from gnomAD v4.1.

How common is CLC p.Leu91Pro (c.272T>C) in the general population?

CLC p.Leu91Pro (c.272T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLC p.Leu91Pro (c.272T>C)?

AlphaMissense predicts likely pathogenic (score 0.788) — an in-silico prediction, not a clinical call.

CLC p.Leu91Pro

c.272T>C · rs2514764335 · VCV3145334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.788 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.788	likely pathogenic
REVEL	0.162	moderately benign-leaning
SaProt	LLR -15.55	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 1.1	GERP 1, phastCons 0.005
Overall
CADD	19.08	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLC
Protein: p.Leu91Pro
Coding: c.272T>C
MANE Select: NM_001828
dbSNP: rs2514764335
Type: single nucleotide variant
Location: chr19:39734314 (GRCh38)
Structure: AlphaFold pLDDT 82.59 · 2 PDB
Residue 91: an α-helix

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

Similar variants

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
CLCF1 p.Arg30Cys Likely 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-leu91pro (accessed [today's date]).

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