Is CDHR5 p.Thr528Ile (c.1583C>T) pathogenic?

CDHR5 p.Thr528Ile (c.1583C>T) is classified Uncertain significance in CDHR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: likely benign (0.1166); Ultra-rare (popmax 0.0268%, eas).

How common is CDHR5 p.Thr528Ile (c.1583C>T) in the general population?

CDHR5 p.Thr528Ile (c.1583C>T) is ultra-rare (popmax 0.0268%, eas) (gnomAD).

What do computational predictors say about CDHR5 p.Thr528Ile (c.1583C>T)?

AlphaMissense predicts likely benign (score 0.1166) — an in-silico prediction, not a clinical call.

CDHR5 p.Thr528Ile

c.1583C>T · rs371167637 · VCV3141413

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1166 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0268%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1166	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -12.14	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.15	GERP -0.068
Regional constraint	o/e 1.11	unconstrained · MANE · 7,548 bp · p 0.00028 · regional, not allelic
Overall
CADD	15.72	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 0.0268% East Asian · 12/44,848 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.0018% 29/1,613,728 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0268%	3,737
South Asian	0.011%	9,106
Remaining individualsnot grpmax-eligible	0.0032%	31,249
Admixed American	0.00167%	60,004
European (non-Finnish)	0.000339%	294,949

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: CDHR5
Protein: p.Thr528Ile
Coding: c.1583C>T
MANE Select: NM_021924
dbSNP: rs371167637
Type: single nucleotide variant
Location: chr11:618976 (GRCh38)
Gene constraint: LOEUF 1.479 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.84 · 1 PDB
Residue 528: the 'disordered' region

Full CDHR5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDHR5 p.Arg182His Benign ★★ same type
CDHR5 p.Gly298= Benign ★★ same type
CDHR5 p.Ala151Pro Uncertain significance ★ ⚠ same type
CDHR5 p.Ala171Thr Uncertain significance ★ ⚠ same type
CDHR5 p.Ala230Thr Uncertain significance ★ ⚠ same type
CDHR5 p.Ala347Val Uncertain significance ★ ⚠ same type
CDHR5 p.Ala364Val Uncertain significance ★ ⚠ same type
CDHR5 p.Ala369Val 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/cdhr5-p-thr528ile (accessed [today's date]).

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