Is CLMN p.Arg90Pro (c.269G>C) pathogenic?

CLMN p.Arg90Pro (c.269G>C) is classified Uncertain significance in CLMN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-30). AlphaMissense: likely pathogenic (0.9936); Absent from gnomAD v4.1.

How common is CLMN p.Arg90Pro (c.269G>C) in the general population?

CLMN p.Arg90Pro (c.269G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLMN p.Arg90Pro (c.269G>C)?

AlphaMissense predicts likely pathogenic (score 0.9936) — an in-silico prediction, not a clinical call.

CLMN p.Arg90Pro

c.269G>C · VCV3493804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9936 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9936	likely pathogenic · top 1% in CLMN
REVEL	0.694	pathogenic-leaning
SaProt	LLR -13.60	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 128 kb · p 0.024 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLMN
Protein: p.Arg90Pro
Coding: c.269G>C
MANE Select: NM_024734
Type: single nucleotide variant
Location: chr14:95221746 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.84
Residue 90: the calponin-homology (ch) 1 domain; the 'actin-binding' region

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

Similar variants

CLMN p.Arg90Cys Uncertain significance ★ ⚠ same residue
CLMN p.Arg90Gly Uncertain significance ★ ⚠ same residue
CLMN p.Arg90His 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

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-arg90pro (accessed [today's date]).

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