Is CLMN p.Pro963Leu (c.2888C>T) pathogenic?

CLMN p.Pro963Leu (c.2888C>T) is classified Benign in CLMN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0767); Low-frequency (popmax 3.43%, afr).

How common is CLMN p.Pro963Leu (c.2888C>T) in the general population?

CLMN p.Pro963Leu (c.2888C>T) is low-frequency (popmax 3.43%, afr) (gnomAD).

What do computational predictors say about CLMN p.Pro963Leu (c.2888C>T)?

AlphaMissense predicts likely benign (score 0.0767) — an in-silico prediction, not a clinical call.

CLMN p.Pro963Leu

c.2888C>T · rs10149705 · VCV786255

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0767 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.43%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0767	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -5.62	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 1.2	GERP -4.9, phastCons 0.02
Regional constraint	o/e 0.94	unconstrained · MANE · 128 kb · p 0.024 · regional, not allelic
Overall
CADD	14.1	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 3.43% African / African-American · 2,574/74,946 alleles

Filtering AF 3.32% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.28%

Overall 0.179% 2,890/1,612,860 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.43%	29
Remaining individualsnot grpmax-eligible	0.223%	449
Admixed American	0.215%	465
Middle Eastern	0.107%	936
South Asian	0.0121%	8,274
East Asian	0.00446%	22,420
European (non-Finnish)	0.00246%	40,683

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.Pro963Leu
Coding: c.2888C>T
MANE Select: NM_024734
dbSNP: rs10149705
Type: single nucleotide variant
Location: chr14:95191685 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.84
Residue 963: a UniProt-annotated variant site (in)

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-pro963leu (accessed [today's date]).

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