Is DCHS2 p.Arg263Trp (c.787C>T) pathogenic?

DCHS2 p.Arg263Trp (c.787C>T) is classified Likely benign in DCHS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-04-01). AlphaMissense: likely benign (0.0983); Rare (popmax 0.67%, amr).

How common is DCHS2 p.Arg263Trp (c.787C>T) in the general population?

DCHS2 p.Arg263Trp (c.787C>T) is rare (popmax 0.67%, amr) (gnomAD).

What do computational predictors say about DCHS2 p.Arg263Trp (c.787C>T)?

AlphaMissense predicts likely benign (score 0.0983) — an in-silico prediction, not a clinical call.

DCHS2 p.Arg263Trp

c.787C>T · rs199621086 · VCV2655144

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0983 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.67%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0983	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.32	GERP -4.5, phastCons 0.091
Regional constraint	o/e 1.03	unconstrained · MANE · 257 kb · p 0.063 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.67% Admixed American · 341/50,930 alleles

Filtering AF 0.611% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.588%

Overall 0.455% 7,027/1,542,874 alleles · rare exomes 6,500/1,390,542 · genomes 527/152,332 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.97%	51
Admixed Americangrpmax	0.67%	149
European (non-Finnish)	0.541%	185
Remaining individualsnot grpmax-eligible	0.43%	233
Middle Eastern	0.368%	272
Ashkenazi Jewishnot grpmax-eligible	0.171%	584
Finnishnot grpmax-eligible	0.118%	845
African / African-American	0.082%	1,219
South Asian	0.0238%	4,198

Amish 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: DCHS2
Protein: p.Arg263Trp
Coding: c.787C>T
MANE Select: NM_001358235
dbSNP: rs199621086
Type: single nucleotide variant
Location: chr4:154490569 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Residue 263: the cadherin 2 domain

Full DCHS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DCHS2 c.2053-13744T>A Uncertain significance ★ same type
DCHS2 c.2053-13798T>C Uncertain significance ★ same type
DCHS2 c.2053-13820G>A Uncertain significance ★ same type
DCHS2 c.2053-13834C>G Uncertain significance ★ same type
DCHS2 c.2244+3317A>T Uncertain significance ★ same type
DCHS2 c.2476+8901A>C Uncertain significance ★ same type
DCHS2 c.2477-1G>T Uncertain significance ★ same type
DCHS2 c.3730+872C>T 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/dchs2-p-arg263trp (accessed [today's date]).

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