Is NIT2 p.Leu6Phe (c.18G>C) pathogenic?

NIT2 p.Leu6Phe (c.18G>C) is classified Uncertain significance in NIT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely benign (0.2472); Ultra-rare (popmax 0.0161%, nfe).

How common is NIT2 p.Leu6Phe (c.18G>C) in the general population?

NIT2 p.Leu6Phe (c.18G>C) is ultra-rare (popmax 0.0161%, nfe) (gnomAD).

What do computational predictors say about NIT2 p.Leu6Phe (c.18G>C)?

AlphaMissense predicts likely benign (score 0.2472) — an in-silico prediction, not a clinical call.

NIT2 p.Leu6Phe

c.18G>C · VCV3919905

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2472 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0161%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2472	likely benign
REVEL	0.685	pathogenic-leaning
SaProt	LLR -12.13	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 20 kb · p 0.07 · regional, not allelic
Overall
CADD	24.0	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 0.0161% European (non-Finnish) · 190/1,177,876 alleles

Filtering AF 0.0142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.012% 194/1,611,634 alleles · ultra-rare exomes 187/1,459,504 · genomes 7/152,130 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0161%	6,199
African / African-American	0.00534%	18,711

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.Leu6Phe
Coding: c.18G>C
MANE Select: NM_020202
Type: single nucleotide variant
Location: chr3:100339097 (GRCh38)
Gene constraint: LOEUF 1.249 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.62
Residue 6: 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-leu6phe (accessed [today's date]).

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