Is CDHR5 p.Val133Ala (c.398T>C) pathogenic?

CDHR5 p.Val133Ala (c.398T>C) is classified Uncertain significance in CDHR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-19). AlphaMissense: likely pathogenic (0.6058); Ultra-rare (popmax 0.0737%, sas).

How common is CDHR5 p.Val133Ala (c.398T>C) in the general population?

CDHR5 p.Val133Ala (c.398T>C) is ultra-rare (popmax 0.0737%, sas) (gnomAD).

What do computational predictors say about CDHR5 p.Val133Ala (c.398T>C)?

AlphaMissense predicts likely pathogenic (score 0.6058) — an in-silico prediction, not a clinical call.

CDHR5 p.Val133Ala

c.398T>C · rs546482155 · VCV2612853

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6058 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0737%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6058	likely pathogenic
REVEL	0.181	moderately benign-leaning
SaProt	LLR -11.79	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 7,548 bp · p 0.00028 · regional, not allelic
Overall
CADD	23.5	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 0.0737% South Asian · 67/90,922 alleles

Filtering AF 0.0594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0543%

Overall 0.00434% 70/1,611,756 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0737%	1,357
Remaining individualsnot grpmax-eligible	0.0048%	20,815

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: CDHR5
Protein: p.Val133Ala
Coding: c.398T>C
MANE Select: NM_021924
dbSNP: rs546482155
Type: single nucleotide variant
Location: chr11:621819 (GRCh38)
Gene constraint: LOEUF 1.479 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.84 · 1 PDB
Residue 133: the cadherin 2 domain; a β-strand

Full CDHR5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDHR5 p.Arg182His Benign ★★ same type
CDHR5 p.Gly298= Benign ★★ same type
CDHR5 p.Ala151Pro Uncertain significance ★ ⚠ same type
CDHR5 p.Ala171Thr Uncertain significance ★ ⚠ same type
CDHR5 p.Ala230Thr Uncertain significance ★ ⚠ same type
CDHR5 p.Ala347Val Uncertain significance ★ ⚠ same type
CDHR5 p.Ala364Val Uncertain significance ★ ⚠ same type
CDHR5 p.Ala369Val Uncertain significance ★ ⚠ 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/cdhr5-p-val133ala (accessed [today's date]).

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