Is DCHS1 p.Arg2330Pro (c.6989G>C) pathogenic?

DCHS1 p.Arg2330Pro (c.6989G>C) is classified Uncertain significance in DCHS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-04). AlphaMissense: likely pathogenic (0.6237); Very rare (popmax 8.48e-05%, nfe).

How common is DCHS1 p.Arg2330Pro (c.6989G>C) in the general population?

DCHS1 p.Arg2330Pro (c.6989G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about DCHS1 p.Arg2330Pro (c.6989G>C)?

AlphaMissense predicts likely pathogenic (score 0.6237) — an in-silico prediction, not a clinical call.

DCHS1 p.Arg2330Pro

c.6989G>C · VCV3671550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6237 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.6237	likely pathogenic
REVEL	0.29	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 18 kb · p 1.2e-10 · regional, not allelic
Overall
CADD	24.1	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 8.48e-05% European (non-Finnish) · 1/1,179,808 alleles

Overall 0.000657% 1/152,198 alleles · very rare

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: DCHS1
Protein: p.Arg2330Pro
Coding: c.6989G>C
MANE Select: NM_003737
Type: single nucleotide variant
Location: chr11:6625355 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.33 · ClinGen HI 1/3 (gnomAD)
Residue 2330: the cadherin 22 domain; a UniProt-annotated variant site (in mvp2; loss-of-function mutation; results in reduced protein levels; results in increased protein degradation)

Full DCHS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DCHS1 p.Arg2330Cys Pathogenic/Likely pathogenic ★★ ⚠ same residue
DCHS1 p.Arg2330His Uncertain significance ★★ ⚠ same residue
DCHS1 p.Arg2141Ter Pathogenic/Likely pathogenic ★★ same type
DCHS1 p.Ala1241Val Uncertain significance ★★ same type
DCHS1 p.Ala1325Ser Uncertain significance ★★ ⚠ same type
DCHS1 p.Ala142Thr Uncertain significance ★★ ⚠ same type
DCHS1 p.Ala1454Val Uncertain significance ★★ ⚠ same type
DCHS1 p.Ala1460Pro 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/dchs1-p-arg2330pro (accessed [today's date]).

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