Is CDHR1 p.Arg726Ser (c.2176C>A) pathogenic?

CDHR1 p.Arg726Ser (c.2176C>A) is classified Uncertain significance in CDHR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). AlphaMissense: likely pathogenic (0.6719); Very rare (popmax 0.0022%, sas).

How common is CDHR1 p.Arg726Ser (c.2176C>A) in the general population?

CDHR1 p.Arg726Ser (c.2176C>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CDHR1 p.Arg726Ser (c.2176C>A)?

AlphaMissense predicts likely pathogenic (score 0.6719) — an in-silico prediction, not a clinical call.

CDHR1 p.Arg726Ser

c.2176C>A · rs141706561 · VCV1422440

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6719	likely pathogenic
REVEL	0.33	indeterminate
SaProt	LLR -8.17	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 4.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 20 kb · p 0.035 · regional, not allelic
Overall
CADD	27.8	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 0.0022% South Asian · 2/91,090 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00097%

Overall 0.00155% 25/1,614,050 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,545
European (non-Finnish)	0.00178%	56,193
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00133%	74,948

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.Arg726Ser
Coding: c.2176C>A
MANE Select: NM_033100
dbSNP: rs141706561
Type: single nucleotide variant
Location: chr10:84214217 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.79

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

Similar variants

CDHR1 p.Arg726Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CDHR1 p.Arg726His Uncertain significance ★ ⚠ 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

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-arg726ser (accessed [today's date]).

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