Is DCHS2 p.Arg425Leu (c.1274G>T) pathogenic?

DCHS2 p.Arg425Leu (c.1274G>T) is classified Likely benign in DCHS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-02-01). AlphaMissense: likely benign (0.1047); Rare (popmax 0.663%, nfe).

How common is DCHS2 p.Arg425Leu (c.1274G>T) in the general population?

DCHS2 p.Arg425Leu (c.1274G>T) is rare (popmax 0.663%, nfe) (gnomAD).

What do computational predictors say about DCHS2 p.Arg425Leu (c.1274G>T)?

AlphaMissense predicts likely benign (score 0.1047) — an in-silico prediction, not a clinical call.

DCHS2 p.Arg425Leu

c.1274G>T · rs201027235 · VCV2655143

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1047 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.663%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.1047	likely benign
REVEL	0.008	strongly benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.78	GERP -0.93
Regional constraint	o/e 1.03	unconstrained · MANE · 257 kb · p 0.063 · regional, not allelic
Overall
CADD	10.04	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 0.663% European (non-Finnish) · 7,604/1,146,788 alleles

Filtering AF 0.651% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.645%

Overall 0.564% 8,747/1,549,542 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.663%	151
Finnishnot grpmax-eligible	0.593%	169
Remaining individualsnot grpmax-eligible	0.448%	223
South Asian	0.373%	268
Admixed American	0.212%	472
Middle Eastern	0.134%	748
Ashkenazi Jewishnot grpmax-eligible	0.112%	895
African / African-American	0.0916%	1,092
East Asian	0.00245%	40,846

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.Arg425Leu
Coding: c.1274G>T
MANE Select: NM_001358235
dbSNP: rs201027235
Type: single nucleotide variant
Location: chr4:154490082 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Residue 425: the cadherin 4 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-arg425leu (accessed [today's date]).

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