Is CLTCL1 p.Ala2Val (c.5C>T) pathogenic?

CLTCL1 p.Ala2Val (c.5C>T) is classified Conflicting classifications of pathogenicity in CLTCL1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-09-17). AlphaMissense: likely benign (0.2979); Rare (popmax 0.231%, nfe).

How common is CLTCL1 p.Ala2Val (c.5C>T) in the general population?

CLTCL1 p.Ala2Val (c.5C>T) is rare (popmax 0.231%, nfe) (gnomAD).

What do computational predictors say about CLTCL1 p.Ala2Val (c.5C>T)?

AlphaMissense predicts likely benign (score 0.2979) — an in-silico prediction, not a clinical call.

CLTCL1 p.Ala2Val

c.5C>T · rs371789769 · VCV2352643

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2979 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.231%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2979	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -9.75	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 2.9	GERP 1.7, phastCons 0.2
Regional constraint	o/e 0.92	unconstrained · MANE · 111 kb · p 0.00057 · regional, not allelic
Overall
CADD	20.7	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 0.231% European (non-Finnish) · 2,451/1,062,932 alleles

Filtering AF 0.223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.22%

Overall 0.18% 2,525/1,399,770 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.231%	434
Remaining individualsnot grpmax-eligible	0.0888%	1,126
Finnishnot grpmax-eligible	0.0223%	4,493
African / African-American	0.018%	5,569
Admixed American	0.00829%	12,068
South Asian	0.00152%	65,674

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: CLTCL1
Protein: p.Ala2Val
Coding: c.5C>T
MANE Select: NM_007098
dbSNP: rs371789769
Type: single nucleotide variant
Location: chr22:19291637 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.53
Residue 2: a modified residue (n-acetylalanine); the 'globular terminal domain' region

Full CLTCL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLTCL1 p.Arg1226Cys Uncertain significance ★★ ⚠ same type
CLTCL1 p.Gln1113Lys Uncertain significance ★★ ⚠ same type
CLTCL1 p.Gln1142Arg Uncertain significance ★★ ⚠ same type
CLTCL1 p.Glu1212Lys Uncertain significance ★★ ⚠ same type
CLTCL1 p.Gly464Arg Uncertain significance ★★ ⚠ same type
CLTCL1 p.Ser1061Gly Uncertain significance ★★ ⚠ same type
CLTCL1 p.Ser707Gly Uncertain significance ★★ ⚠ same type
CLTCL1 p.Val948Gly 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/cltcl1-p-ala2val (accessed [today's date]).

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