Is CLC p.His41Tyr (c.121C>T) pathogenic?

CLC p.His41Tyr (c.121C>T) is classified Uncertain significance in CLC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-12). AlphaMissense: likely benign (0.1213); Very rare (popmax 0.0011%, sas).

How common is CLC p.His41Tyr (c.121C>T) in the general population?

CLC p.His41Tyr (c.121C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CLC p.His41Tyr (c.121C>T)?

AlphaMissense predicts likely benign (score 0.1213) — an in-silico prediction, not a clinical call.

CLC p.His41Tyr

c.121C>T · rs776178968 · VCV2516631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1213 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1213	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP 1
Overall
CADD	6.008	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000805% 13/1,614,024 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,086
European (non-Finnish)	0.00102%	98,332

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.His41Tyr
Coding: c.121C>T
MANE Select: NM_013246 · reported on NM_001828
dbSNP: rs776178968
Type: single nucleotide variant
Location: chr19:39734465 (GRCh38)
Structure: AlphaFold pLDDT 82.59 · 2 PDB
Residue 41: 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-his41tyr (accessed [today's date]).

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