Is CLMN p.Arg90Cys (c.268C>T) pathogenic?

CLMN p.Arg90Cys (c.268C>T) is classified Uncertain significance in CLMN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely pathogenic (0.9257); Very rare (popmax 0.00576%, nfe).

How common is CLMN p.Arg90Cys (c.268C>T) in the general population?

CLMN p.Arg90Cys (c.268C>T) is very rare (popmax 0.00576%, nfe) (gnomAD).

What do computational predictors say about CLMN p.Arg90Cys (c.268C>T)?

AlphaMissense predicts likely pathogenic (score 0.9257) — an in-silico prediction, not a clinical call.

CLMN p.Arg90Cys

c.268C>T · rs112023847 · VCV2211308

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9257 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00576%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9257	likely pathogenic · top 7% in CLMN
REVEL	0.78	moderately pathogenic-leaning
SaProt	LLR -11.63	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 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 128 kb · p 0.024 · regional, not allelic
Overall
CADD	34.0	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

Grpmax group 0.00576% European (non-Finnish) · 68/1,180,022 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00422%

Overall 0.00682% 110/1,613,996 alleles · very rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	4.28%	23
European (non-Finnish)grpmax	0.00576%	17,353
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
African / African-American	0.00267%	37,454

Amish 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: CLMN
Protein: p.Arg90Cys
Coding: c.268C>T
MANE Select: NM_024734
dbSNP: rs112023847
Type: single nucleotide variant
Location: chr14:95221747 (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.Arg90Gly Uncertain significance ★ ⚠ same residue
CLMN p.Arg90His Uncertain significance ★ ⚠ same residue
CLMN p.Arg90Pro 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-arg90cys (accessed [today's date]).

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