Is CLCA2 p.Ser751Pro (c.2251T>C) pathogenic?

CLCA2 p.Ser751Pro (c.2251T>C) is classified Uncertain significance in CLCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-28). AlphaMissense: likely benign (0.258); Very rare (popmax 0.00161%, nfe).

How common is CLCA2 p.Ser751Pro (c.2251T>C) in the general population?

CLCA2 p.Ser751Pro (c.2251T>C) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about CLCA2 p.Ser751Pro (c.2251T>C)?

AlphaMissense predicts likely benign (score 0.258) — an in-silico prediction, not a clinical call.

CLCA2 p.Ser751Pro

c.2251T>C · rs763147874 · VCV2210663

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.258	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -11.34	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.44	GERP -0.8, phastCons 0.014
Regional constraint	o/e 0.97	unconstrained · MANE · 31 kb · p 0.29 · regional, not allelic
Overall
CADD	22.1	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 0.00161% European (non-Finnish) · 19/1,180,038 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00149% 24/1,614,068 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)grpmax	0.00161%	62,107
African / African-American	0.00133%	74,934

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser751Pro
Coding: c.2251T>C
MANE Select: NM_006536
dbSNP: rs763147874
Type: single nucleotide variant
Location: chr1:86453464 (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.Ser751Thr Uncertain significance ★ ⚠ same residue
CLCA2 p.Leu169Phe Uncertain significance ★★ ⚠ same type
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

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-ser751pro (accessed [today's date]).

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