Is NHS p.Pro36Ser (c.106C>T) pathogenic?

NHS p.Pro36Ser (c.106C>T) is classified Uncertain significance in NHS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-01). Very rare (popmax 0.00597%, amr); Associated with Nance-Horan syndrome.

What condition is associated with NHS p.Pro36Ser (c.106C>T)?

NHS p.Pro36Ser (c.106C>T) is associated with Nance-Horan syndrome (ClinVar).

How common is NHS p.Pro36Ser (c.106C>T) in the general population?

NHS p.Pro36Ser (c.106C>T) is very rare (popmax 0.00597%, amr) (gnomAD).

NHS p.Pro36Ser

c.106C>T · rs893345497 · VCV2047505

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00597%, amr)

Conditions

Nance-Horan syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.054	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 0.87, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 357 kb · p 1.3e-14 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00597% Admixed American · 2/33,514 alleles

Filtering AF 0.004% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00357%

Overall 0.00429% 48/1,117,704 alleles · very rare exomes 43/1,005,498 · genomes 5/112,206 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00597%	16,757
European (non-Finnish)	0.00525%	19,065
Remaining individualsnot grpmax-eligible	0.00227%	44,008

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: NHS
Protein: p.Pro36Ser
Coding: c.106C>T
MANE Select: NM_001291867
dbSNP: rs893345497
Type: single nucleotide variant
Location: chrX:17375863 (GRCh38)
Structure: AlphaFold pLDDT 43.65
Residue 36: the 'wave homology domain (whd)' region; the 'disordered' region

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

Disease context

Nance-Horan syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NHS p.Arg248Ter Pathogenic ★★ same condition
NHS p.Arg394Ter Pathogenic ★★ same condition
NHS p.Arg900Ter Pathogenic ★★ same condition
NHS p.Gln411Ter Pathogenic ★★ same condition
NHS p.Gln80Ter Pathogenic/Likely pathogenic ★★ same condition
NHS p.Ala564Val Uncertain significance ★★ same condition
NHS p.Ala745Val Uncertain significance ★★ same condition
NHS p.Arg162Cys 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/nhs-p-pro36ser (accessed [today's date]).

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