Is CHST6 p.Arg209Cys (c.625C>T) pathogenic?

CHST6 p.Arg209Cys (c.625C>T) is classified Uncertain significance in CHST6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-16). AlphaMissense: ambiguous (0.3691); Very rare (popmax 0.00133%, afr); Associated with macular corneal dystrophy.

What condition is associated with CHST6 p.Arg209Cys (c.625C>T)?

CHST6 p.Arg209Cys (c.625C>T) is associated with macular corneal dystrophy (ClinVar).

How common is CHST6 p.Arg209Cys (c.625C>T) in the general population?

CHST6 p.Arg209Cys (c.625C>T) is very rare (popmax 0.00133%, afr) (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.Arg209Cys (c.625C>T)?

AlphaMissense predicts ambiguous (score 0.3691) — an in-silico prediction, not a clinical call.

CHST6 p.Arg209Cys

c.625C>T · rs769402722 · VCV2151729

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3691 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

macular corneal dystrophy

Computational evidence

Protein change
AlphaMissense	0.3691	ambiguous
REVEL	0.66	pathogenic-leaning
SaProt	LLR -11.66	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP -1.1, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 1,184 bp · p 3.9e-06 · regional, not allelic
Overall
CADD	27.8	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 0.00133% African / African-American · 1/75,028 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000275% 4/1,457,002 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,404
African / African-Americangrpmax	0.00133%	75,028
European (non-Finnish)	0.00017%	589,633

Remaining individuals 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: CHST6
Protein: p.Arg209Cys
Coding: c.625C>T
MANE Select: NM_021615
dbSNP: rs769402722
Type: single nucleotide variant
Location: chr16:75479204 (GRCh38)
Gene constraint: LOEUF 1.71 · pLI 0.26 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.66
Residue 209: a binding site

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.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
CHST6 p.Glu274Lys Pathogenic ★★ same condition
CHST6 p.Leu200Arg 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-arg209cys (accessed [today's date]).

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