Is CHST6 p.Leu348Arg (c.1043T>G) pathogenic?

CHST6 p.Leu348Arg (c.1043T>G) is classified Uncertain significance in CHST6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-04). AlphaMissense: likely benign (0.1185); Rare (popmax 0.198%, mid); Associated with macular corneal dystrophy.

What condition is associated with CHST6 p.Leu348Arg (c.1043T>G)?

CHST6 p.Leu348Arg (c.1043T>G) is associated with macular corneal dystrophy (ClinVar).

How common is CHST6 p.Leu348Arg (c.1043T>G) in the general population?

CHST6 p.Leu348Arg (c.1043T>G) is rare (popmax 0.198%, mid) (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.Leu348Arg (c.1043T>G)?

AlphaMissense predicts likely benign (score 0.1185) — an in-silico prediction, not a clinical call.

CHST6 p.Leu348Arg

c.1043T>G · rs189849720 · VCV1044629

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1185 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.198%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

macular corneal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1185	likely benign
REVEL	0.6	indeterminate
SaProt	LLR -9.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	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	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.198% Middle Eastern · 12/6,062 alleles

Filtering AF 0.131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.121%

Overall 0.0325% 525/1,613,512 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.198%	505
Admixed American	0.157%	639
Remaining individualsnot grpmax-eligible	0.112%	893
African / African-American	0.0306%	3,264
European (non-Finnish)	0.0275%	3,642
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,586
South Asian	0.0011%	91,086

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.Leu348Arg
Coding: c.1043T>G
MANE Select: NM_021615
dbSNP: rs189849720
Type: single nucleotide variant
Location: chr16:75478786 (GRCh38)
Gene constraint: LOEUF 1.71 · pLI 0.26 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.66

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.Leu348Val Uncertain significance ★ ⚠ 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
CHST6 p.Glu274Lys 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-leu348arg (accessed [today's date]).

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