Is CLCA4 p.Ile355Val (c.1063A>G) pathogenic?

CLCA4 p.Ile355Val (c.1063A>G) is classified Uncertain significance in CLCA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: likely benign (0.0677); Ultra-rare (popmax 0.0165%, mid).

How common is CLCA4 p.Ile355Val (c.1063A>G) in the general population?

CLCA4 p.Ile355Val (c.1063A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CLCA4 p.Ile355Val (c.1063A>G)?

AlphaMissense predicts likely benign (score 0.0677) — an in-silico prediction, not a clinical call.

CLCA4 p.Ile355Val

c.1063A>G · rs2101807016 · VCV2547634

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0677 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0677	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -5.47	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 -1.9	GERP -3.2
Regional constraint	o/e 1.03	unconstrained · MANE · 33 kb · p 0.26 · regional, not allelic
Overall
CADD	0.02	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,192 alleles · ultra-rare exomes 3/1,461,052 · genomes 0/152,140 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
European (non-Finnish)	0.00017%	589,644

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: CLCA4
Protein: p.Ile355Val
Coding: c.1063A>G
MANE Select: NM_012128
dbSNP: rs2101807016
Type: single nucleotide variant
Location: chr1:86567532 (GRCh38)
Gene constraint: LOEUF 1.078 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48
Residue 355: the vwfa domain

Full CLCA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCA4 p.Asp510Gly Uncertain significance ★★ ⚠ same type
CLCA4 p.Gln485Ter Uncertain significance ★★ same type
CLCA4 p.Arg113= Benign/Likely benign ★★ same type
CLCA4 p.Ala235Thr Uncertain significance ★ ⚠ same type
CLCA4 p.Ala353Val Uncertain significance ★ same type
CLCA4 p.Ala431Thr Uncertain significance ★ ⚠ same type
CLCA4 p.Ala431Val Uncertain significance ★ ⚠ same type
CLCA4 p.Ala437Gly 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/clca4-p-ile355val (accessed [today's date]).

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