Is DCHS1 p.Ala2769= (c.8307G>A) pathogenic?

DCHS1 p.Ala2769= (c.8307G>A) is classified Benign in DCHS1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 20.7%, nfe) — too common for a highly-penetrant pathogenic allele.

DCHS1 p.Ala2769=

Q: How common is DCHS1 p.Ala2769= (c.8307G>A) in the general population?

DCHS1 p.Ala2769= (c.8307G>A) is common (popmax 20.7%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.8307G>A · rs72911011 · VCV1225638

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 20.7%, nfe) — too common for a highly-penetrant pathogenic allele

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 -0.47	GERP -2.4, phastCons 0.17
Overall
CADD	3.373	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 20.7% European (non-Finnish) · 242,026/1,171,168 alleles

Filtering AF 20.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 20.6%

Overall 19.3% 307,613/1,596,098 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	24.9%	4
European (non-Finnish)grpmax	20.7%	5
Remaining individualsnot grpmax-eligible	17.3%	6
Admixed American	16.9%	6
Ashkenazi Jewishnot grpmax-eligible	16.3%	6
Middle Eastern	13.8%	7
Amishnot grpmax-eligible	12.7%	8
South Asian	12.5%	8
East Asian	11.6%	9
African / African-American	10.4%	10

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: DCHS1
Protein: p.Ala2769=
Coding: c.8307G>A
MANE Select: NM_003737
dbSNP: rs72911011
Type: single nucleotide variant
Location: chr11:6623369 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.33 · ClinGen HI 1/3 (gnomAD)
Residue 2769: the cadherin 26 domain

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

Similar variants

DCHS1 p.Ala2769Val Uncertain significance ★ ⚠ same residue
DCHS1 p.Arg2141Ter Pathogenic/Likely pathogenic ★★ same type
DCHS1 p.Arg2330Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
DCHS1 p.Ala1241Val Uncertain significance ★★ same type
DCHS1 p.Ala1325Ser Uncertain significance ★★ ⚠ same type
DCHS1 p.Ala142Thr Uncertain significance ★★ ⚠ same type
DCHS1 p.Ala1454Val Uncertain significance ★★ ⚠ same type
DCHS1 p.Ala1460Pro 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/dchs1-p-ala2769 (accessed [today's date]).

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