Is CDHR4 p.Pro336Leu (c.1007C>T) pathogenic?

CDHR4 p.Pro336Leu (c.1007C>T) is classified Uncertain significance in CDHR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.4499); Very rare (popmax 0.00881%, nfe).

How common is CDHR4 p.Pro336Leu (c.1007C>T) in the general population?

CDHR4 p.Pro336Leu (c.1007C>T) is very rare (popmax 0.00881%, nfe) (gnomAD).

What do computational predictors say about CDHR4 p.Pro336Leu (c.1007C>T)?

AlphaMissense predicts ambiguous (score 0.4499) — an in-silico prediction, not a clinical call.

CDHR4 p.Pro336Leu

c.1007C>T · rs757390031 · VCV3141395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4499 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00881%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4499	ambiguous
REVEL	0.684	pathogenic-leaning
SaProt	LLR -11.60	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 8,977 bp · p 0.0033 · regional, not allelic
Overall
CADD	25.3	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 0.00881% European (non-Finnish) · 101/1,146,988 alleles

Filtering AF 0.00737% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00687%

Overall 0.00703% 109/1,551,562 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00881%	11,356
Finnishnot grpmax-eligible	0.00501%	19,962
African / African-American	0.00411%	24,347
Remaining individualsnot grpmax-eligible	0.00333%	30,046

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.Pro336Leu
Coding: c.1007C>T
MANE Select: NM_001007540
dbSNP: rs757390031
Type: single nucleotide variant
Location: chr3:49795220 (GRCh38)
Gene constraint: LOEUF 1.174 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.90
Residue 336: the cadherin 1 domain

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-pro336leu (accessed [today's date]).

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