Is CLMN p.Pro346Gln (c.1037C>A) pathogenic?

CLMN p.Pro346Gln (c.1037C>A) is classified Uncertain significance in CLMN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-28). AlphaMissense: ambiguous (0.4883); Ultra-rare (popmax 0.08%, afr).

How common is CLMN p.Pro346Gln (c.1037C>A) in the general population?

CLMN p.Pro346Gln (c.1037C>A) is ultra-rare (popmax 0.08%, afr) (gnomAD).

What do computational predictors say about CLMN p.Pro346Gln (c.1037C>A)?

AlphaMissense predicts ambiguous (score 0.4883) — an in-silico prediction, not a clinical call.

CLMN p.Pro346Gln

c.1037C>A · VCV3493797

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4883 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.08%, afr)

Computational evidence

Protein change
AlphaMissense	0.4883	ambiguous
REVEL	0.524	indeterminate
SaProt	LLR -6.11	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 128 kb · p 0.024 · regional, not allelic
Overall
CADD	26.8	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 0.08% African / African-American · 60/74,998 alleles

Filtering AF 0.0637% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0579%

Overall 0.00372% 60/1,614,074 alleles · ultra-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: CLMN
Protein: p.Pro346Gln
Coding: c.1037C>A
MANE Select: NM_024734
Type: single nucleotide variant
Location: chr14:95204312 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.84

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

Similar variants

CLMN p.Pro346Arg Uncertain significance ★ ⚠ same residue
CLMN c.2511+10C>T Benign ★★ same type
CLMN c.886-4G>T Likely benign ★★ same type
CLMN p.Asp592= Benign ★★ same type
CLMN p.Glu276Lys Likely benign ★★ same type
CLMN p.Glu357Lys Benign ★★ same type
CLMN p.Glu771Ala Likely benign ★★ ⚠ same type
CLMN p.His518= Benign ★★ 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/clmn-p-pro346gln (accessed [today's date]).

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