Is NDST1 p.Val227= (c.681T>G) pathogenic?

NDST1 p.Val227= (c.681T>G) is classified Benign in NDST1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Common (popmax 54.1%, amr) — too common for a highly-penetrant pathogenic allele; Associated with intellectual disability, autosomal recessive 46.

What condition is associated with NDST1 p.Val227= (c.681T>G)?

NDST1 p.Val227= (c.681T>G) is associated with intellectual disability, autosomal recessive 46 (ClinVar).

NDST1 p.Val227=

Q: How common is NDST1 p.Val227= (c.681T>G) in the general population?

NDST1 p.Val227= (c.681T>G) is common (popmax 54.1%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.681T>G · rs2273235 · VCV1302756

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 54.1%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

intellectual disability, autosomal recessive 46

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.22	GERP -5.7, phastCons 0.92
Overall
CADD	6.765	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 54.1% Admixed American · 32,406/59,940 alleles

Filtering AF 53.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 53.4%

Overall 45.5% 733,799/1,613,472 alleles · common exomes 670,317/1,461,432 · genomes 63,482/152,040 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	56.9%	2
Admixed Americangrpmax	54.1%	2
European (non-Finnish)	46.7%	2
Amishnot grpmax-eligible	45.6%	2
South Asian	43.2%	2
Remaining individualsnot grpmax-eligible	43.2%	2
Ashkenazi Jewishnot grpmax-eligible	33%	3
East Asian	31.7%	3
Middle Eastern	30.7%	3
African / African-American	28%	4

Finnish 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: NDST1
Protein: p.Val227=
Coding: c.681T>G
MANE Select: NM_001543
dbSNP: rs2273235
Type: single nucleotide variant
Location: chr5:150527971 (GRCh38)
Gene constraint: LOEUF 0.484 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 90.55 · 5 PDB
Residue 227: the 'heparan sulfate n-deacetylase 1' region

Full NDST1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, autosomal recessive 46 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NDST1 p.Gly611Ser Pathogenic/Likely pathogenic ★★ same condition
NDST1 p.Arg112Cys Uncertain significance ★★ ⚠ same condition
NDST1 p.Arg130Cys Uncertain significance ★★ ⚠ same condition
NDST1 p.Arg244Cys Uncertain significance ★★ ⚠ same condition
NDST1 p.Arg454Cys Uncertain significance ★★ ⚠ same condition
NDST1 p.Arg688Gln Uncertain significance ★★ ⚠ same condition
NDST1 p.Arg875Ter Uncertain significance ★★ same condition
NDST1 p.His13Gln Uncertain significance ★★ ⚠ 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/ndst1-p-val227 (accessed [today's date]).

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