Is CHST8 p.Arg77Trp (c.229C>T) pathogenic?

CHST8 p.Arg77Trp (c.229C>T) is classified Conflicting classifications of pathogenicity in CHST8 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-05-07). AlphaMissense: likely benign (0.0789); Rare (popmax 0.674%, nfe); Associated with peeling skin syndrome type A.

What condition is associated with CHST8 p.Arg77Trp (c.229C>T)?

CHST8 p.Arg77Trp (c.229C>T) is associated with peeling skin syndrome type A (ClinVar).

How common is CHST8 p.Arg77Trp (c.229C>T) in the general population?

CHST8 p.Arg77Trp (c.229C>T) is rare (popmax 0.674%, nfe) (gnomAD).

How is Generalized peeling skin syndrome inherited?

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

What do computational predictors say about CHST8 p.Arg77Trp (c.229C>T)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

CHST8 p.Arg77Trp

c.229C>T · rs149660944 · VCV183645

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.674%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

peeling skin syndrome type A

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.401	indeterminate
SaProt	LLR -8.40	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 -0.71	GERP -0.66
Regional constraint	o/e 1.04	unconstrained · MANE · 84 kb · p 0.3 · regional, not allelic
Overall
CADD	14.59	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 0.674% European (non-Finnish) · 7,939/1,178,616 alleles

Filtering AF 0.661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.656%

Overall 0.57% 9,173/1,609,794 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.674%	148
Remaining individualsnot grpmax-eligible	0.541%	185
South Asian	0.523%	191
Admixed American	0.282%	355
Finnishnot grpmax-eligible	0.267%	374
Middle Eastern	0.116%	864
African / African-American	0.101%	985
Ashkenazi Jewishnot grpmax-eligible	0.0136%	7,340
East Asian	0.00223%	44,818

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: CHST8
Protein: p.Arg77Trp
Coding: c.229C>T
MANE Select: NM_001127895
dbSNP: rs149660944
Type: single nucleotide variant
Location: chr19:33772017 (GRCh38)
Gene constraint: LOEUF 1.001 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.90
Residue 77: a UniProt-annotated variant site (according to pubmed:22289416 this variant results in decreased glycosaminoglycan sulfation; according to pubmed:28204496 it does not affect sulfotransferase activity); the 'disordered' region

Full CHST8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

peeling skin syndrome type A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Generalized peeling skin syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

CHST8 p.Arg77= Likely benign same residue
CHST8 p.Val186Ala Uncertain significance ★★ ⚠ same type
CHST8 c.168+64G>A Benign ★★ same type
CHST8 c.-86-36C>T Benign ★★ same type
CHST8 p.Arg9= Benign ★★ same type
CHST8 p.Leu288= Benign ★★ same type
CHST8 p.Ala23Gly Uncertain significance ★ ⚠ same type
CHST8 p.Ala293Pro 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/chst8-p-arg77trp (accessed [today's date]).

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