Is DCHS2 p.Phe771Ser (c.2312T>C) pathogenic?

DCHS2 p.Phe771Ser (c.2312T>C) is classified Uncertain significance in DCHS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely pathogenic (0.9751); Ultra-rare (popmax 0.0174%, afr).

How common is DCHS2 p.Phe771Ser (c.2312T>C) in the general population?

DCHS2 p.Phe771Ser (c.2312T>C) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about DCHS2 p.Phe771Ser (c.2312T>C)?

AlphaMissense predicts likely pathogenic (score 0.9751) — an in-silico prediction, not a clinical call.

DCHS2 p.Phe771Ser

c.2312T>C · VCV3500050

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9751 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.9751	likely pathogenic · top 1% in DCHS2
REVEL	0.853	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 257 kb · p 0.063 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0174% African / African-American · 13/74,878 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.000868% 14/1,613,828 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,760
South Asian	0.0011%	91,066

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.Phe771Ser
Coding: c.2312T>C
MANE Select: NM_001358235
Type: single nucleotide variant
Location: chr4:154366374 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Residue 771: the cadherin 6 domain

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

Similar variants

DCHS2 c.2053-13744T>A Uncertain significance ★ same type
DCHS2 c.2053-13798T>C Uncertain significance ★ same type
DCHS2 c.2053-13820G>A Uncertain significance ★ same type
DCHS2 c.2053-13834C>G Uncertain significance ★ same type
DCHS2 c.2244+3317A>T Uncertain significance ★ same type
DCHS2 c.2476+8901A>C Uncertain significance ★ same type
DCHS2 c.2477-1G>T Uncertain significance ★ same type
DCHS2 c.3730+872C>T 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/dchs2-p-phe771ser (accessed [today's date]).

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