Is DCHS1 p.Pro1300Ser (c.3898C>T) pathogenic?

DCHS1 p.Pro1300Ser (c.3898C>T) is classified Uncertain significance in DCHS1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-31). AlphaMissense: likely benign (0.1038); Ultra-rare (popmax 0.0133%, afr); Associated with van Maldergem syndrome 1.

What condition is associated with DCHS1 p.Pro1300Ser (c.3898C>T)?

DCHS1 p.Pro1300Ser (c.3898C>T) is associated with van Maldergem syndrome 1, mitral valve prolapse, myxomatous 2 (ClinVar).

How common is DCHS1 p.Pro1300Ser (c.3898C>T) in the general population?

DCHS1 p.Pro1300Ser (c.3898C>T) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about DCHS1 p.Pro1300Ser (c.3898C>T)?

AlphaMissense predicts likely benign (score 0.1038) — an in-silico prediction, not a clinical call.

DCHS1 p.Pro1300Ser

c.3898C>T · rs201667197 · VCV1493677

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1038 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

van Maldergem syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1038	likely benign
REVEL	0.126	moderately 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 10	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 18 kb · p 1.2e-10 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% African / African-American · 10/75,008 alleles

Filtering AF 0.00722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.000682% 11/1,611,858 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,501
European (non-Finnish)	8.49e-05%	1,178,370

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.Pro1300Ser
Coding: c.3898C>T
MANE Select: NM_003737
dbSNP: rs201667197
Type: single nucleotide variant
Location: chr11:6631085 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.33 · ClinGen HI 1/3 (gnomAD)
Residue 1300: the cadherin 12 domain

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

Disease context

van Maldergem syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitral valve prolapse, myxomatous 2

Similar variants

DCHS1 p.Pro1300His Uncertain significance ★ ⚠ same residue
DCHS1 p.Pro1300Thr 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.Ala2815Thr 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-pro1300ser (accessed [today's date]).

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