Is CLCA2 p.Thr845= (c.2535G>A) pathogenic?

CLCA2 p.Thr845= (c.2535G>A) is classified Benign in CLCA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-11). Common (popmax 5.63%, afr) — too common for a highly-penetrant pathogenic allele.

CLCA2 p.Thr845=

Q: How common is CLCA2 p.Thr845= (c.2535G>A) in the general population?

CLCA2 p.Thr845= (c.2535G>A) is common (popmax 5.63%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2535G>A · rs75217405 · VCV783291

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 5.63%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.67	GERP -1.2
Overall
CADD	6.637	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.63% African / African-American · 4,221/74,998 alleles

Filtering AF 5.49% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.43%

Overall 0.301% 4,864/1,614,020 alleles · common exomes 2,453/1,461,796 · genomes 2,411/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.63%	18
Remaining individualsnot grpmax-eligible	0.45%	222
Admixed American	0.367%	273
Middle Eastern	0.313%	319
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,960
South Asian	0.011%	9,108
European (non-Finnish)	0.00873%	11,456

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.Thr845=
Coding: c.2535G>A
MANE Select: NM_006536
dbSNP: rs75217405
Type: single nucleotide variant
Location: chr1:86455230 (GRCh38)
Gene constraint: LOEUF 1.144 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.87

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

Similar variants

CLCA2 p.Leu169Phe Uncertain significance ★★ ⚠ same type
CLCA2 p.Gln842= 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-thr845 (accessed [today's date]).

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