Is NIT2 p.Pro134Leu (c.401C>T) pathogenic?

NIT2 p.Pro134Leu (c.401C>T) is classified Uncertain significance in NIT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: ambiguous (0.361); Very rare (popmax 0.00467%, nfe).

How common is NIT2 p.Pro134Leu (c.401C>T) in the general population?

NIT2 p.Pro134Leu (c.401C>T) is very rare (popmax 0.00467%, nfe) (gnomAD).

What do computational predictors say about NIT2 p.Pro134Leu (c.401C>T)?

AlphaMissense predicts ambiguous (score 0.361) — an in-silico prediction, not a clinical call.

NIT2 p.Pro134Leu

c.401C>T · rs756067624 · VCV2359652

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.361 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00467%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.361	ambiguous
REVEL	0.75	pathogenic-leaning
SaProt	LLR -12.27	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 20 kb · p 0.07 · regional, not allelic
Overall
CADD	31.0	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 0.00467% European (non-Finnish) · 55/1,178,812 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00366% 59/1,612,382 alleles · very rare exomes 55/1,460,254 · genomes 4/152,128 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00467%	21,433
Admixed American	0.00167%	59,972
Remaining individualsnot grpmax-eligible	0.0016%	62,418
African / African-American	0.00134%	74,884
South Asian	0.0011%	90,908

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: NIT2
Protein: p.Pro134Leu
Coding: c.401C>T
MANE Select: NM_020202
dbSNP: rs756067624
Type: single nucleotide variant
Location: chr3:100345649 (GRCh38)
Gene constraint: LOEUF 1.249 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.62
Residue 134: the cn hydrolase domain

Full NIT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NIT2 p.Ala209Val Uncertain significance ★ ⚠ same type
NIT2 p.Ala51Gly Uncertain significance ★ ⚠ same type
NIT2 p.Ala51Val Uncertain significance ★ ⚠ same type
NIT2 p.Arg157Gln Uncertain significance ★ ⚠ same type
NIT2 p.Arg195Trp Uncertain significance ★ ⚠ same type
NIT2 p.Arg210Trp Uncertain significance ★ same type
NIT2 p.Arg23Cys Uncertain significance ★ ⚠ same type
NIT2 p.Arg255Cys 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/nit2-p-pro134leu (accessed [today's date]).

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