Is NSUN2 p.Pro474= (c.1422G>A) pathogenic?

NSUN2 p.Pro474= (c.1422G>A) is classified Conflicting classifications of pathogenicity in NSUN2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-01). Ultra-rare (popmax 0.0493%, mid); Associated with intellectual disability, autosomal recessive 5.

What condition is associated with NSUN2 p.Pro474= (c.1422G>A)?

NSUN2 p.Pro474= (c.1422G>A) is associated with intellectual disability, autosomal recessive 5 (ClinVar).

How common is NSUN2 p.Pro474= (c.1422G>A) in the general population?

NSUN2 p.Pro474= (c.1422G>A) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

NSUN2 p.Pro474=

c.1422G>A · rs1055478673 · VCV589252

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Conditions

intellectual disability, autosomal recessive 5

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 -0.87	GERP -3.5
Overall
CADD	4.572	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00896%

Overall 0.0204% 329/1,614,066 alleles · ultra-rare exomes 297/1,461,876 · genomes 32/152,190 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.524%	191
Middle Easterngrpmax	0.0493%	2,028
Remaining individualsnot grpmax-eligible	0.0432%	2,314
European (non-Finnish)	0.0111%	9,008
African / African-American	0.00801%	12,489
South Asian	0.00549%	18,218
East Asian	0.00223%	44,900
Admixed American	0.00167%	60,000

Ashkenazi Jewish 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: NSUN2
Protein: p.Pro474=
Coding: c.1422G>A
MANE Select: NM_017755
dbSNP: rs1055478673
Type: single nucleotide variant
Location: chr5:6607286 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.09 · 11 PDB
Residue 474: the 'disordered' region

Full NSUN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, autosomal recessive 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NSUN2 p.Pro474Leu Uncertain significance ★ ⚠ same residue
NSUN2 p.Arg389Ter Pathogenic/Likely pathogenic ★★ same condition
NSUN2 c.1226+4A>T Uncertain significance ★★ same condition
NSUN2 c.255-4A>G Uncertain significance ★★ same condition
NSUN2 p.Asn547Asp Uncertain significance ★★ ⚠ same condition
NSUN2 p.Asp669Gly Uncertain significance ★★ ⚠ same condition
NSUN2 p.Cys678Gly Uncertain significance ★★ ⚠ same condition
NSUN2 p.Gly255Ser 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/nsun2-p-pro474 (accessed [today's date]).

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