Is NSD3 p.Pro130Ala (c.388C>G) pathogenic?

NSD3 p.Pro130Ala (c.388C>G) is classified Uncertain significance in NSD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-06). AlphaMissense: likely benign (0.0741); Very rare (popmax 0.00439%, sas).

How common is NSD3 p.Pro130Ala (c.388C>G) in the general population?

NSD3 p.Pro130Ala (c.388C>G) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about NSD3 p.Pro130Ala (c.388C>G)?

AlphaMissense predicts likely benign (score 0.0741) — an in-silico prediction, not a clinical call.

NSD3 p.Pro130Ala

c.388C>G · rs1426067826 · VCV1331507

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0741 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0741	likely benign
REVEL	0.37	indeterminate
SaProt	LLR -7.12	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 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 446 bp · p 2.4e-05 · regional, not allelic
Overall
CADD	22.7	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 0.00439% South Asian · 4/91,078 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000274% 4/1,461,398 alleles · very rare

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: NSD3
Protein: p.Pro130Ala
Coding: c.388C>G
MANE Select: NM_023034
dbSNP: rs1426067826
Type: single nucleotide variant
Location: chr8:38347784 (GRCh38)
Gene constraint: LOEUF 0.176 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.29 · 25 PDB
Residue 130: the 'disordered' region

Full NSD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NSD3 p.Ala1212= Benign ★★ same type
NSD3 p.Arg383Pro Benign ★★ same type
NSD3 p.Asn987= Benign ★★ same type
NSD3 p.Ser754Leu Benign ★★ same type
NSD3 p.Ser855Gly Benign ★★ same type
NSD3 p.Thr186Met Benign ★★ same type
NSD3 p.Thr556Met Likely benign ★★ same type
NSD3 c.1855+1G>A 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/nsd3-p-pro130ala (accessed [today's date]).

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