Is CDHR2 p.Ser281Phe (c.842C>T) pathogenic?

CDHR2 p.Ser281Phe (c.842C>T) is classified Uncertain significance in CDHR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-15). AlphaMissense: likely benign (0.2428); Rare (popmax 0.511%, mid).

How common is CDHR2 p.Ser281Phe (c.842C>T) in the general population?

CDHR2 p.Ser281Phe (c.842C>T) is rare (popmax 0.511%, mid) (gnomAD).

What do computational predictors say about CDHR2 p.Ser281Phe (c.842C>T)?

AlphaMissense predicts likely benign (score 0.2428) — an in-silico prediction, not a clinical call.

CDHR2 p.Ser281Phe

c.842C>T · rs144549731 · VCV2324825

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2428 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.511%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2428	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -9.99	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 4.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 19 kb · p 0.025 · regional, not allelic
Overall
CADD	26.9	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 0.511% Middle Eastern · 31/6,062 alleles

Filtering AF 0.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.322%

Overall 0.0352% 568/1,614,068 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.511%	196
Remaining individualsnot grpmax-eligible	0.08%	1,250
Admixed American	0.0666%	1,501
European (non-Finnish)	0.0358%	2,796
South Asian	0.022%	4,554
African / African-American	0.00666%	15,009

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: CDHR2
Protein: p.Ser281Phe
Coding: c.842C>T
MANE Select: NM_017675
dbSNP: rs144549731
Type: single nucleotide variant
Location: chr5:176575579 (GRCh38)
Gene constraint: LOEUF 0.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 2 PDB
Residue 281: the cadherin 3 domain

Full CDHR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDHR2 p.Ala1162Thr Uncertain significance ★ ⚠ same type
CDHR2 p.Ala121Thr Uncertain significance ★ ⚠ same type
CDHR2 p.Ala13Val Uncertain significance ★ ⚠ same type
CDHR2 p.Ala415Thr Uncertain significance ★ ⚠ same type
CDHR2 p.Ala423Thr Uncertain significance ★ ⚠ same type
CDHR2 p.Ala512Thr Uncertain significance ★ ⚠ same type
CDHR2 p.Ala652Thr Uncertain significance ★ ⚠ same type
CDHR2 p.Ala656Thr 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/cdhr2-p-ser281phe (accessed [today's date]).

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