Is NOTCH2 p.Pro54Ala (c.160C>G) pathogenic?

NOTCH2 p.Pro54Ala (c.160C>G) is classified Likely benign in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: likely benign (0.1087); Ultra-rare (popmax 0.0971%, eas); Associated with Inborn genetic diseases.

What condition is associated with NOTCH2 p.Pro54Ala (c.160C>G)?

NOTCH2 p.Pro54Ala (c.160C>G) is associated with Inborn genetic diseases (ClinVar).

How common is NOTCH2 p.Pro54Ala (c.160C>G) in the general population?

NOTCH2 p.Pro54Ala (c.160C>G) is ultra-rare (popmax 0.0971%, eas) (gnomAD).

What do computational predictors say about NOTCH2 p.Pro54Ala (c.160C>G)?

AlphaMissense predicts likely benign (score 0.1087) — an in-silico prediction, not a clinical call.

NOTCH2 p.Pro54Ala

c.160C>G · VCV3406938

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1087 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0971%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1087	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -7.26	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 7.7	phastCons 1
Regional constraint	o/e 0.23	constrained · MANE · 64 kb · p 3.4e-08 · regional, not allelic
Overall
CADD	16.17	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 0.0971% East Asian · 43/44,298 alleles

Filtering AF 0.074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0659%

Overall 0.00283% 44/1,554,204 alleles · ultra-rare exomes 35/1,411,106 · genomes 9/143,098 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0971%	1,030
Admixed American	0.00172%	58,234

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: NOTCH2
Protein: p.Pro54Ala
Coding: c.160C>G
MANE Select: NM_024408
Type: single nucleotide variant
Location: chr1:120005584 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 54: the egf-like 1 domain

Full NOTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH2 p.Pro54Leu Uncertain significance ★ ⚠ same residue
NOTCH2 p.Arg2003Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 p.Ala1416Gly Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Arg1231Gln Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Arg1231Trp Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Arg1718His Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Arg1801Ser Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Arg1824Cys 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/notch2-p-pro54ala (accessed [today's date]).

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