Is DCHS2 p.Pro209Ser (c.625C>T) pathogenic?

DCHS2 p.Pro209Ser (c.625C>T) is classified Benign in DCHS2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-05-01). AlphaMissense: likely benign (0.0846); Common (popmax 9.02%, amr) — too common for a highly-penetrant pathogenic allele; Associated with DCHS2-related disorder.

What condition is associated with DCHS2 p.Pro209Ser (c.625C>T)?

DCHS2 p.Pro209Ser (c.625C>T) is associated with DCHS2-related disorder (ClinVar).

What do computational predictors say about DCHS2 p.Pro209Ser (c.625C>T)?

AlphaMissense predicts likely benign (score 0.0846) — an in-silico prediction, not a clinical call.

DCHS2 p.Pro209Ser

Q: How common is DCHS2 p.Pro209Ser (c.625C>T) in the general population?

DCHS2 p.Pro209Ser (c.625C>T) is common (popmax 9.02%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.625C>T · rs17373860 · VCV3059143

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0846 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 9.02%, amr) — 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	0.0846	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.019	GERP -3.6
Regional constraint	o/e 1.03	unconstrained · MANE · 257 kb · p 0.063 · regional, not allelic
Overall
CADD	1.596	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 9.02% Admixed American · 4,601/51,014 alleles

Filtering AF 8.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.71%

Overall 6.92% 107,380/1,551,632 alleles · common exomes 98,531/1,399,302 · genomes 8,849/152,330 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	15%	7
Amishnot grpmax-eligible	12.4%	8
Admixed Americangrpmax	9.02%	11
European (non-Finnish)	7.44%	13
Remaining individualsnot grpmax-eligible	5.77%	17
Ashkenazi Jewishnot grpmax-eligible	3.82%	26
South Asian	3.42%	29
Middle Eastern	1.72%	58
African / African-American	1.08%	92
East Asian	0.066%	1,515

Finnish 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.Pro209Ser
Coding: c.625C>T
MANE Select: NM_001358235
dbSNP: rs17373860
Type: single nucleotide variant
Location: chr4:154490731 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Residue 209: the cadherin 2 domain

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

Disease context

DCHS2-related disorder

Similar variants

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
DCHS2 c.2477-8381C>T 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-pro209ser (accessed [today's date]).

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