Is DCHS1 p.Arg2139Trp (c.6415C>T) pathogenic?

DCHS1 p.Arg2139Trp (c.6415C>T) is classified Uncertain significance in DCHS1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-08). AlphaMissense: likely benign (0.1702); Ultra-rare (popmax 0.0293%, afr); Associated with mitral valve prolapse, myxomatous 2.

What condition is associated with DCHS1 p.Arg2139Trp (c.6415C>T)?

DCHS1 p.Arg2139Trp (c.6415C>T) is associated with mitral valve prolapse, myxomatous 2 (ClinVar).

How common is DCHS1 p.Arg2139Trp (c.6415C>T) in the general population?

DCHS1 p.Arg2139Trp (c.6415C>T) is ultra-rare (popmax 0.0293%, afr) (gnomAD).

What do computational predictors say about DCHS1 p.Arg2139Trp (c.6415C>T)?

AlphaMissense predicts likely benign (score 0.1702) — an in-silico prediction, not a clinical call.

DCHS1 p.Arg2139Trp

c.6415C>T · rs145429962 · VCV1033609

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1702 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0293%, afr)

Conditions

mitral valve prolapse, myxomatous 2

Computational evidence

Protein change
AlphaMissense	0.1702	likely benign
REVEL	0.329	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 18 kb · p 1.2e-10 · regional, not allelic
Overall
CADD	27.2	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 0.0293% African / African-American · 22/75,058 alleles

Filtering AF 0.0198% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00248% 40/1,613,524 alleles · ultra-rare exomes 31/1,461,176 · genomes 9/152,348 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0293%	3,412
Middle Eastern	0.0165%	6,062
Admixed American	0.00667%	14,992
South Asian	0.0044%	22,735
Remaining individualsnot grpmax-eligible	0.0032%	31,236
European (non-Finnish)	0.000593%	168,528

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.Arg2139Trp
Coding: c.6415C>T
MANE Select: NM_003737
dbSNP: rs145429962
Type: single nucleotide variant
Location: chr11:6626330 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.33 · ClinGen HI 1/3 (gnomAD)
Residue 2139: the cadherin 20 domain

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

Disease context

mitral valve prolapse, myxomatous 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DCHS1 p.Arg2139Gln Uncertain significance ★ ⚠ same residue
DCHS1 p.Arg2330Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
DCHS1 p.Ala1325Ser Uncertain significance ★★ ⚠ same condition
DCHS1 p.Ala1600Ser Uncertain significance ★★ ⚠ same condition
DCHS1 p.Ala1937Ser Uncertain significance ★★ ⚠ same condition
DCHS1 p.Ala2550Glu Uncertain significance ★★ ⚠ same condition
DCHS1 p.Ala2817Pro Uncertain significance ★★ ⚠ same condition
DCHS1 p.Ala444Ser Uncertain significance ★★ 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/dchs1-p-arg2139trp (accessed [today's date]).

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