Is DCHS1 p.Arg646Gly (c.1936C>G) pathogenic?

DCHS1 p.Arg646Gly (c.1936C>G) is classified Conflicting classifications of pathogenicity in DCHS1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-10). AlphaMissense: likely pathogenic (0.7837); Very rare (popmax 0.00668%, amr).

How common is DCHS1 p.Arg646Gly (c.1936C>G) in the general population?

DCHS1 p.Arg646Gly (c.1936C>G) is very rare (popmax 0.00668%, amr) (gnomAD).

What do computational predictors say about DCHS1 p.Arg646Gly (c.1936C>G)?

AlphaMissense predicts likely pathogenic (score 0.7837) — an in-silico prediction, not a clinical call.

DCHS1 p.Arg646Gly

c.1936C>G · rs199875933 · VCV1672752

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7837 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, amr)

Computational evidence

Protein change
AlphaMissense	0.7837	likely pathogenic
REVEL	0.492	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 18 kb · p 1.2e-10 · regional, not allelic
Overall
CADD	26.0	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 0.00668% Admixed American · 4/59,892 alleles

Filtering AF 0.0024% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.0146% 235/1,612,214 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.545%	183
Remaining individualsnot grpmax-eligible	0.0513%	1,949
Admixed Americangrpmax	0.00668%	14,973
European (non-Finnish)	0.00322%	31,017

Ashkenazi Jewish 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: DCHS1
Protein: p.Arg646Gly
Coding: c.1936C>G
MANE Select: NM_003737
dbSNP: rs199875933
Type: single nucleotide variant
Location: chr11:6634168 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.33 · ClinGen HI 1/3 (gnomAD)
Residue 646: the cadherin 6 domain

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

Similar variants

DCHS1 p.Arg646His Uncertain significance ★ same residue
DCHS1 p.Arg646Leu Uncertain significance ★ same residue
DCHS1 p.Arg2141Ter Pathogenic/Likely pathogenic ★★ same type
DCHS1 p.Arg2330Cys 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

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-arg646gly (accessed [today's date]).

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