Is CDHR3 p.Ile643Thr (c.1928T>C) pathogenic?

CDHR3 p.Ile643Thr (c.1928T>C) is classified Uncertain significance in CDHR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). AlphaMissense: likely benign (0.0917); Ultra-rare (popmax 0.0346%, afr).

How common is CDHR3 p.Ile643Thr (c.1928T>C) in the general population?

CDHR3 p.Ile643Thr (c.1928T>C) is ultra-rare (popmax 0.0346%, afr) (gnomAD).

What do computational predictors say about CDHR3 p.Ile643Thr (c.1928T>C)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

CDHR3 p.Ile643Thr

c.1928T>C · VCV4224088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0346%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -7.14	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 -0.059	GERP 2.8, phastCons 0.005
Regional constraint	o/e 1.00	unconstrained · MANE · 69 kb · p 0.92 · regional, not allelic
Overall
CADD	12.89	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 0.0346% African / African-American · 26/75,068 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00173% 28/1,614,066 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0346%	2,887
Admixed American	0.00167%	60,026
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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: CDHR3
Protein: p.Ile643Thr
Coding: c.1928T>C
MANE Select: NM_152750
Type: single nucleotide variant
Location: chr7:106022300 (GRCh38)
Gene constraint: LOEUF 1.087 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.08 · 3 PDB
Residue 643: the cadherin 6 domain

Full CDHR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDHR3 c.1653+3G>A Benign/Likely benign ★★ same type
CDHR3 p.Arg603Cys Likely benign ★★ ⚠ same type
CDHR3 p.Asp337= Benign ★★ same type
CDHR3 p.Gln399= Benign ★★ same type
CDHR3 p.Ala148Ser Uncertain significance ★ ⚠ same type
CDHR3 p.Ala158Asp Uncertain significance ★ ⚠ same type
CDHR3 p.Ala541Asp Uncertain significance ★ ⚠ same type
CDHR3 p.Ala541Val 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/cdhr3-p-ile643thr (accessed [today's date]).

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