Is NOTUM p.Pro35Ser (c.103C>T) pathogenic?

NOTUM p.Pro35Ser (c.103C>T) is classified Uncertain significance in NOTUM (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely benign (0.0663); Ultra-rare (popmax 0.0816%, mid).

How common is NOTUM p.Pro35Ser (c.103C>T) in the general population?

NOTUM p.Pro35Ser (c.103C>T) is ultra-rare (popmax 0.0816%, mid) (gnomAD).

What do computational predictors say about NOTUM p.Pro35Ser (c.103C>T)?

AlphaMissense predicts likely benign (score 0.0663) — an in-silico prediction, not a clinical call.

NOTUM p.Pro35Ser

c.103C>T · rs746150888 · VCV2395163

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0663 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0816%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0663	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -7.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 1.1, phastCons 0.14
Regional constraint	o/e 0.95	unconstrained · MANE · 7,945 bp · p 0.18 · regional, not allelic
Overall
CADD	19.23	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 0.0816% Middle Eastern · 4/4,902 alleles

Filtering AF 0.0278% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00525% 81/1,542,296 alleles · ultra-rare exomes 74/1,390,090 · genomes 7/152,206 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0816%	1,226
South Asian	0.0261%	3,835
European (non-Finnish)	0.00436%	22,914
Remaining individualsnot grpmax-eligible	0.00335%	29,861
African / African-American	0.00273%	36,612
Admixed American	0.00195%	51,406

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: NOTUM
Protein: p.Pro35Ser
Coding: c.103C>T
MANE Select: NM_178493
dbSNP: rs746150888
Type: single nucleotide variant
Location: chr17:81960807 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.47 · 141 PDB
Residue 35: the 'disordered' region

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

Similar variants

NOTUM p.Pro35Arg Uncertain significance ★ ⚠ same residue
NOTUM p.Cys285= Benign/Likely benign ★★ same type
NOTUM p.Ala205Ser Uncertain significance ★ ⚠ same type
NOTUM p.Ala205Thr Uncertain significance ★ ⚠ same type
NOTUM p.Ala229Thr Uncertain significance ★ ⚠ same type
NOTUM p.Ala290Thr Uncertain significance ★ ⚠ same type
NOTUM p.Ala74Val Uncertain significance ★ ⚠ same type
NOTUM p.Arg145His 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/notum-p-pro35ser (accessed [today's date]).

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