Is CDHR1 p.Val458Asp (c.1373T>A) pathogenic?

CDHR1 p.Val458Asp (c.1373T>A) is classified Conflicting classifications of pathogenicity in CDHR1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-22). AlphaMissense: likely pathogenic (0.9908); Ultra-rare (popmax 0.0329%, mid); Associated with cone-rod dystrophy 15.

What condition is associated with CDHR1 p.Val458Asp (c.1373T>A)?

CDHR1 p.Val458Asp (c.1373T>A) is associated with cone-rod dystrophy 15, cone-rod dystrophy (ClinVar).

How common is CDHR1 p.Val458Asp (c.1373T>A) in the general population?

CDHR1 p.Val458Asp (c.1373T>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

How is Cone rod dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDHR1 p.Val458Asp (c.1373T>A)?

AlphaMissense predicts likely pathogenic (score 0.9908) — an in-silico prediction, not a clinical call.

CDHR1 p.Val458Asp

c.1373T>A · rs760942217 · VCV812260

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9908 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cone-rod dystrophy 15

Computational evidence

Protein change
AlphaMissense	0.9908	likely pathogenic · top 1% in CDHR1
REVEL	0.714	pathogenic-leaning
SaProt	LLR -18.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	29.2	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000496% 8/1,614,080 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
European (non-Finnish)	0.000508%	196,673

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.Val458Asp
Coding: c.1373T>A
MANE Select: NM_033100
dbSNP: rs760942217
Type: single nucleotide variant
Location: chr10:84211053 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.79
Residue 458: the cadherin 4 domain

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

Disease context

cone-rod dystrophy 15 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cone-rod dystrophy

For Cone rod dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDHR1 c.1485+2T>G Pathogenic ★★ same condition
CDHR1 c.525+1G>A Pathogenic ★★ same condition
CDHR1 c.56-1G>A Pathogenic/Likely pathogenic ★★ same condition
CDHR1 c.863-1G>A Pathogenic/Likely pathogenic ★★ same condition
CDHR1 p.Arg407Ter Pathogenic ★★ same condition
CDHR1 p.Gln461Ter Pathogenic ★★ same condition
CDHR1 p.Lys582Ter Pathogenic/Likely pathogenic ★★ same condition
CDHR1 c.1554-3C>A Uncertain significance ★★ same condition

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-val458asp (accessed [today's date]).

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