Is CBLN2 p.Val136Ala (c.407T>C) pathogenic?

CBLN2 p.Val136Ala (c.407T>C) is classified Uncertain significance in CBLN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely benign (0.2557); Very rare (popmax 0.000254%, nfe).

How common is CBLN2 p.Val136Ala (c.407T>C) in the general population?

CBLN2 p.Val136Ala (c.407T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CBLN2 p.Val136Ala (c.407T>C)?

AlphaMissense predicts likely benign (score 0.2557) — an in-silico prediction, not a clinical call.

CBLN2 p.Val136Ala

c.407T>C · rs1400271031 · VCV3138015

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2557 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2557	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -8.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 3,273 bp · p 0.018 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000254% European (non-Finnish) · 3/1,180,000 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,002 alleles · very rare exomes 3/1,461,722 · genomes 0/152,280 · joint denominator

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: CBLN2
Protein: p.Val136Ala
Coding: c.407T>C
MANE Select: NM_182511
dbSNP: rs1400271031
Type: single nucleotide variant
Location: chr18:72538723 (GRCh38)
Gene constraint: LOEUF 1.118 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 77.19
Residue 136: the c1q domain

Full CBLN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBLN2 p.Val136Ile Uncertain significance ★ ⚠ same residue
CBLN2 c.-115C>G Benign ★★ same type
CBLN2 c.-166-135C>A Likely benign ★★ same type
CBLN2 c.-166-77G>A Benign ★★ same type
CBLN2 c.-85A>G Benign ★★ same type
CBLN2 c.*10C>T Benign ★★ same type
CBLN2 p.Pro25= Benign ★★ same type
CBLN2 p.Ser73= 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/cbln2-p-val136ala (accessed [today's date]).

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