Is NIT2 p.Arg195Trp (c.583C>T) pathogenic?

NIT2 p.Arg195Trp (c.583C>T) is classified Uncertain significance in NIT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-22). AlphaMissense: likely pathogenic (0.8384); Ultra-rare (popmax 0.033%, mid).

How common is NIT2 p.Arg195Trp (c.583C>T) in the general population?

NIT2 p.Arg195Trp (c.583C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about NIT2 p.Arg195Trp (c.583C>T)?

AlphaMissense predicts likely pathogenic (score 0.8384) — an in-silico prediction, not a clinical call.

NIT2 p.Arg195Trp

c.583C>T · VCV3299845

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8384 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8384	likely pathogenic
REVEL	0.854	moderately pathogenic-leaning
SaProt	LLR -17.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.79	GERP -1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 20 kb · p 0.07 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.033% Middle Eastern · 2/6,066 alleles

Filtering AF 0.00945% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00888%

Overall 0.00886% 143/1,613,318 alleles · ultra-rare exomes 133/1,461,170 · genomes 10/152,148 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,033
European (non-Finnish)	0.011%	9,073
Admixed American	0.005%	19,992
Remaining individualsnot grpmax-eligible	0.0048%	20,815
African / African-American	0.00401%	24,962
East Asian	0.00223%	44,868
South Asian	0.0011%	91,060

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.Arg195Trp
Coding: c.583C>T
MANE Select: NM_020202
Type: single nucleotide variant
Location: chr3:100348880 (GRCh38)
Gene constraint: LOEUF 1.249 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.62
Residue 195: 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.Arg210Trp Uncertain significance ★ same type
NIT2 p.Arg23Cys Uncertain significance ★ ⚠ same type
NIT2 p.Arg255Cys Uncertain significance ★ ⚠ same type
NIT2 p.Arg29Trp 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-arg195trp (accessed [today's date]).

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