Is CDHR1 p.Phe452Leu (c.1354T>C) pathogenic?

CDHR1 p.Phe452Leu (c.1354T>C) is classified Conflicting classifications of pathogenicity in CDHR1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-21). AlphaMissense: likely pathogenic (0.968); Ultra-rare (popmax 0.099%, mid).

How common is CDHR1 p.Phe452Leu (c.1354T>C) in the general population?

CDHR1 p.Phe452Leu (c.1354T>C) is ultra-rare (popmax 0.099%, mid) (gnomAD).

What do computational predictors say about CDHR1 p.Phe452Leu (c.1354T>C)?

AlphaMissense predicts likely pathogenic (score 0.968) — an in-silico prediction, not a clinical call.

CDHR1 p.Phe452Leu

c.1354T>C · rs112631930 · VCV833694

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.968 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.968	likely pathogenic · top 3% in CDHR1
REVEL	0.218	benign-leaning
SaProt	LLR -4.08	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 4.6, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 20 kb · p 0.035 · regional, not allelic
Overall
CADD	27.2	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 0.099% Middle Eastern · 6/6,062 alleles

Filtering AF 0.059% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0533%

Overall 0.0146% 235/1,614,152 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.099%	1,010
Remaining individualsnot grpmax-eligible	0.0816%	1,226
African / African-American	0.0746%	1,340
Admixed American	0.0533%	1,875
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,692
European (non-Finnish)	0.00644%	15,527
East Asian	0.00223%	44,876
South Asian	0.0022%	45,541

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: CDHR1
Protein: p.Phe452Leu
Coding: c.1354T>C
MANE Select: NM_033100
dbSNP: rs112631930
Type: single nucleotide variant
Location: chr10:84211034 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.79
Residue 452: the cadherin 4 domain

Full CDHR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDHR1 p.Phe452Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CDHR1 c.1168-1G>C Pathogenic/Likely pathogenic ★★ same type
CDHR1 c.1321-1G>A Likely pathogenic ★★ same type
CDHR1 c.1485+2T>C Pathogenic ★★ same type
CDHR1 c.1485+2T>G Pathogenic ★★ same type
CDHR1 c.1554-2A>C Pathogenic/Likely pathogenic ★★ same type
CDHR1 c.297+1G>T Pathogenic ★★ same type
CDHR1 c.525+1G>A Pathogenic ★★ 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/cdhr1-p-phe452leu (accessed [today's date]).

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