Is DCHS2 p.Arg166Cys (c.496C>T) pathogenic?

DCHS2 p.Arg166Cys (c.496C>T) is classified Benign in DCHS2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-07). AlphaMissense: likely benign (0.1228); Common (popmax 19.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with DCHS2-related disorder.

What condition is associated with DCHS2 p.Arg166Cys (c.496C>T)?

DCHS2 p.Arg166Cys (c.496C>T) is associated with DCHS2-related disorder (ClinVar).

What do computational predictors say about DCHS2 p.Arg166Cys (c.496C>T)?

AlphaMissense predicts likely benign (score 0.1228) — an in-silico prediction, not a clinical call.

DCHS2 p.Arg166Cys

Q: How common is DCHS2 p.Arg166Cys (c.496C>T) in the general population?

DCHS2 p.Arg166Cys (c.496C>T) is common (popmax 19.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.496C>T · rs17031725 · VCV3038189

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1228 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 19.5%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DCHS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1228	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -9.57	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 0.46	GERP -4.2, phastCons 0.031
Regional constraint	o/e 1.03	unconstrained · MANE · 257 kb · p 0.063 · regional, not allelic
Overall
CADD	18.28	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 19.5% African / African-American · 14,293/73,144 alleles

Filtering AF 19.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 19.2%

Overall 1.07% 16,551/1,551,530 alleles · common exomes 8,072/1,399,240 · genomes 8,479/152,290 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	19.5%	5
Remaining individualsnot grpmax-eligible	1.43%	70
Admixed American	1.25%	80
Ashkenazi Jewishnot grpmax-eligible	1.16%	86
Middle Eastern	0.818%	122
South Asian	0.0488%	2,050
European (non-Finnish)	0.0296%	3,383

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.Arg166Cys
Coding: c.496C>T
MANE Select: NM_001358235
dbSNP: rs17031725
Type: single nucleotide variant
Location: chr4:154490860 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Residue 166: the cadherin 1 domain

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

Disease context

DCHS2-related disorder

Similar variants

DCHS2 p.Arg166Gly Benign same residue
DCHS2 c.2477-1G>T Uncertain significance ★ same condition
DCHS2 p.Ala952Thr Uncertain significance same condition
DCHS2 p.Ile802Val Uncertain significance ⚠ same condition
DCHS2 p.Ser1397Phe Uncertain significance ⚠ same condition
DCHS2 c.2053-13755G>A Likely benign same condition
DCHS2 c.2053-13815C>T Benign same condition
DCHS2 c.2244+3329T>C Benign same condition

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-arg166cys (accessed [today's date]).

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