Is DCHS2 p.Leu1069= (c.3205C>T) pathogenic?

DCHS2 p.Leu1069= (c.3205C>T) is classified Benign in DCHS2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-09-06). Rare (popmax 0.346%, mid); Associated with DCHS2-related disorder.

What condition is associated with DCHS2 p.Leu1069= (c.3205C>T)?

DCHS2 p.Leu1069= (c.3205C>T) is associated with DCHS2-related disorder (ClinVar).

How common is DCHS2 p.Leu1069= (c.3205C>T) in the general population?

DCHS2 p.Leu1069= (c.3205C>T) is rare (popmax 0.346%, mid) (gnomAD).

DCHS2 p.Leu1069=

c.3205C>T · rs149462928 · VCV3039585

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.346%, mid)

Conditions

DCHS2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -0.95, phastCons 1
Overall
CADD	6.77	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.346% Middle Eastern · 21/6,062 alleles

Filtering AF 0.232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.195%

Overall 0.0911% 1,470/1,614,150 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.936%	107
Middle Easterngrpmax	0.346%	289
Remaining individualsnot grpmax-eligible	0.162%	619
Admixed American	0.137%	732
European (non-Finnish)	0.0813%	1,230
African / African-American	0.0187%	5,361
South Asian	0.011%	9,109
Finnishnot grpmax-eligible	0.00937%	10,673

Ashkenazi Jewish 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.Leu1069=
Coding: c.3205C>T
MANE Select: NM_001358235
dbSNP: rs149462928
Type: single nucleotide variant
Location: chr4:154333003 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Residue 1069: the cadherin 9 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-leu1069 (accessed [today's date]).

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