Is CDH23 p.Thr1649= (c.4947G>A) pathogenic?

CDH23 p.Thr1649= (c.4947G>A) is classified Likely benign in CDH23 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.078%, nfe).

How common is CDH23 p.Thr1649= (c.4947G>A) in the general population?

CDH23 p.Thr1649= (c.4947G>A) is ultra-rare (popmax 0.078%, nfe) (gnomAD).

CDH23 p.Thr1649=

c.4947G>A · rs373046094 · VCV227226

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.078%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -3.8
Overall
CADD	1.362	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.078% European (non-Finnish) · 920/1,179,842 alleles

Filtering AF 0.0738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0721%

Overall 0.0679% 1,096/1,613,832 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.101%	992
Finnishnot grpmax-eligible	0.0953%	1,049
European (non-Finnish)grpmax	0.078%	1,282
South Asian	0.0307%	3,252
African / African-American	0.0227%	4,413
East Asian	0.00669%	14,957
Admixed American	0.00667%	14,999

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CDH23
Protein: p.Thr1649=
Coding: c.4947G>A
MANE Select: NM_022124
dbSNP: rs373046094
Type: single nucleotide variant
Location: chr10:71777781 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1649: the cadherin 16 domain

Full CDH23 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH23 p.Thr1649Met Uncertain significance ★★ ⚠ same residue
CDH23 p.Arg2029Trp Pathogenic ★★★ ⚠ same type
CDH23 p.Asp127Gly Likely pathogenic ★★★ same type
CDH23 p.Glu956Lys Pathogenic ★★★ same type
CDH23 p.Pro240Leu Pathogenic ★★★ same type
CDH23 c.1515-12G>A Uncertain significance ★★★ same type
CDH23 p.Ala3190Val Uncertain significance ★★★ ⚠ same type
CDH23 p.Arg301Gln 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/cdh23-p-thr1649 (accessed [today's date]).

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