Is CDHR4 p.Val8Met (c.22G>A) pathogenic?

CDHR4 p.Val8Met (c.22G>A) is classified Uncertain significance in CDHR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). AlphaMissense: likely benign (0.1155); Very rare (popmax 0.00432%, nfe).

How common is CDHR4 p.Val8Met (c.22G>A) in the general population?

CDHR4 p.Val8Met (c.22G>A) is very rare (popmax 0.00432%, nfe) (gnomAD).

What do computational predictors say about CDHR4 p.Val8Met (c.22G>A)?

AlphaMissense predicts likely benign (score 0.1155) — an in-silico prediction, not a clinical call.

CDHR4 p.Val8Met

c.22G>A · VCV4651268

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1155 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00432%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1155	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -8.21	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 -0.64	GERP -1.2
Regional constraint	o/e 0.91	unconstrained · MANE · 8,977 bp · p 0.0033 · regional, not allelic
Overall
CADD	1.461	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 0.00432% European (non-Finnish) · 51/1,179,864 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00341% 55/1,613,846 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00432%	23,135
South Asian	0.0022%	45,541
Admixed American	0.00167%	60,008
African / African-American	0.00133%	74,926

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: CDHR4
Protein: p.Val8Met
Coding: c.22G>A
MANE Select: NM_001007540
Type: single nucleotide variant
Location: chr3:49799791 (GRCh38)
Gene constraint: LOEUF 1.174 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.90

Full CDHR4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDHR4 p.Ala12Val Uncertain significance ★ ⚠ same type
CDHR4 p.Ala149Val Uncertain significance ★ ⚠ same type
CDHR4 p.Ala302Val Uncertain significance ★ ⚠ same type
CDHR4 p.Ala310Pro Uncertain significance ★ ⚠ same type
CDHR4 p.Ala318Asp Uncertain significance ★ ⚠ same type
CDHR4 p.Ala341Pro Uncertain significance ★ ⚠ same type
CDHR4 p.Ala385Gly Uncertain significance ★ ⚠ same type
CDHR4 p.Ala456Pro 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/cdhr4-p-val8met (accessed [today's date]).

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