Is CLCA2 p.Leu169Phe (c.505C>T) pathogenic?

CLCA2 p.Leu169Phe (c.505C>T) is classified Uncertain significance in CLCA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-28). AlphaMissense: likely benign (0.0808); Very rare (popmax 0.000254%, nfe).

How common is CLCA2 p.Leu169Phe (c.505C>T) in the general population?

CLCA2 p.Leu169Phe (c.505C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CLCA2 p.Leu169Phe (c.505C>T)?

AlphaMissense predicts likely benign (score 0.0808) — an in-silico prediction, not a clinical call.

CLCA2 p.Leu169Phe

c.505C>T · rs1468138529 · VCV2258993

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0808 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0808	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -9.71	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 2.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 31 kb · p 0.29 · regional, not allelic
Overall
CADD	19.72	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 0.000254% European (non-Finnish) · 3/1,179,754 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,254 alleles · very rare

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: CLCA2
Protein: p.Leu169Phe
Coding: c.505C>T
MANE Select: NM_006536
dbSNP: rs1468138529
Type: single nucleotide variant
Location: chr1:86430891 (GRCh38)
Gene constraint: LOEUF 1.144 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.87
Residue 169: the 'metalloprotease domain' region

Full CLCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCA2 p.Gln842= Benign ★★ same type
CLCA2 p.Thr845= Benign ★★ same type
CLCA2 p.Tyr155= Benign ★★ same type
CLCA2 c.475+2T>A Uncertain significance ★ same type
CLCA2 p.Ala109Val Uncertain significance ★ ⚠ same type
CLCA2 p.Ala238Val Uncertain significance ★ ⚠ same type
CLCA2 p.Ala262Thr Uncertain significance ★ ⚠ same type
CLCA2 p.Ala334Asp 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/clca2-p-leu169phe (accessed [today's date]).

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