Is CLMN p.Pro124Ala (c.370C>G) pathogenic?

CLMN p.Pro124Ala (c.370C>G) is classified Likely benign in CLMN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-07-16). AlphaMissense: likely benign (0.1588); Rare (popmax 0.425%, afr).

How common is CLMN p.Pro124Ala (c.370C>G) in the general population?

CLMN p.Pro124Ala (c.370C>G) is rare (popmax 0.425%, afr) (gnomAD).

What do computational predictors say about CLMN p.Pro124Ala (c.370C>G)?

AlphaMissense predicts likely benign (score 0.1588) — an in-silico prediction, not a clinical call.

CLMN p.Pro124Ala

c.370C>G · rs151018579 · VCV740265

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1588 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.425%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1588	likely benign
REVEL	0.626	indeterminate
SaProt	LLR -4.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 2.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 128 kb · p 0.024 · regional, not allelic
Overall
CADD	24.7	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 0.425% African / African-American · 319/75,026 alleles

Filtering AF 0.387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.372%

Overall 0.0229% 369/1,614,128 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.425%	235
Admixed American	0.0433%	2,308
Remaining individualsnot grpmax-eligible	0.0352%	2,841
European (non-Finnish)	0.000169%	590,012

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.Pro124Ala
Coding: c.370C>G
MANE Select: NM_024734
dbSNP: rs151018579
Type: single nucleotide variant
Location: chr14:95215688 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.84
Residue 124: 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 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
CLMN p.Ile900Phe 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-pro124ala (accessed [today's date]).

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