Is CHST6 p.Leu276Pro (c.827T>C) pathogenic?

CHST6 p.Leu276Pro (c.827T>C) is classified Conflicting classifications of pathogenicity in CHST6 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-21). AlphaMissense: likely pathogenic (0.9643); Very rare (popmax 0.00746%, nfe); Associated with macular corneal dystrophy.

What condition is associated with CHST6 p.Leu276Pro (c.827T>C)?

CHST6 p.Leu276Pro (c.827T>C) is associated with macular corneal dystrophy (ClinVar).

How common is CHST6 p.Leu276Pro (c.827T>C) in the general population?

CHST6 p.Leu276Pro (c.827T>C) is very rare (popmax 0.00746%, nfe) (gnomAD).

How is Macular corneal dystrophy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CHST6 p.Leu276Pro (c.827T>C)?

AlphaMissense predicts likely pathogenic (score 0.9643) — an in-silico prediction, not a clinical call.

CHST6 p.Leu276Pro

c.827T>C · rs121917824 · VCV5078

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00746%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

macular corneal dystrophy

Computational evidence

Protein change
AlphaMissense	0.9643	likely pathogenic · top 5% in CHST6
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -15.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 1,184 bp · p 3.9e-06 · regional, not allelic
Overall
CADD	28.8	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 0.00746% European (non-Finnish) · 88/1,179,938 alleles

Filtering AF 0.00615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00573%

Overall 0.00577% 93/1,611,874 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00746%	13,408
Remaining individualsnot grpmax-eligible	0.0064%	15,617
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,580

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: CHST6
Protein: p.Leu276Pro
Coding: c.827T>C
MANE Select: NM_021615
dbSNP: rs121917824
Type: single nucleotide variant
Location: chr16:75479002 (GRCh38)
Gene constraint: LOEUF 1.71 · pLI 0.26 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.66
Residue 276: a UniProt-annotated variant site (in mcd)

Full CHST6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

macular corneal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Macular corneal dystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (United States)

Similar variants

CHST6 p.Leu276= Benign/Likely benign ★★ same residue
CHST6 p.Leu276fs Likely pathogenic ★ same residue
CHST6 p.Ala128Thr Likely pathogenic ★★ ⚠ same condition
CHST6 p.Arg127Cys Pathogenic ★★ same condition
CHST6 p.Arg140Ter Pathogenic ★★ same condition
CHST6 p.Arg211Gln Pathogenic ★★ ⚠ same condition
CHST6 p.Cys102Gly Pathogenic ★★ same condition
CHST6 p.Gln58Ter Pathogenic/Likely pathogenic ★★ 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/chst6-p-leu276pro (accessed [today's date]).

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