Is NIT1 p.Arg243Trp (c.727C>T) pathogenic?

NIT1 p.Arg243Trp (c.727C>T) is classified Conflicting classifications of pathogenicity in NIT1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-08-05). AlphaMissense: likely pathogenic (0.6923); Ultra-rare (popmax 0.0291%, nfe); Associated with brain small vessel disease 4.

What condition is associated with NIT1 p.Arg243Trp (c.727C>T)?

NIT1 p.Arg243Trp (c.727C>T) is associated with brain small vessel disease 4 (ClinVar).

How common is NIT1 p.Arg243Trp (c.727C>T) in the general population?

NIT1 p.Arg243Trp (c.727C>T) is ultra-rare (popmax 0.0291%, nfe) (gnomAD).

What do computational predictors say about NIT1 p.Arg243Trp (c.727C>T)?

AlphaMissense predicts likely pathogenic (score 0.6923) — an in-silico prediction, not a clinical call.

NIT1 p.Arg243Trp

c.727C>T · rs144065383 · VCV2354724

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6923 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0291%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

brain small vessel disease 4

Computational evidence

Protein change
AlphaMissense	0.6923	likely pathogenic
REVEL	0.551	indeterminate
SaProt	LLR -14.43	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.87, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 2,585 bp · p 0.18 · regional, not allelic
Overall
CADD	25.9	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 0.0291% European (non-Finnish) · 343/1,179,720 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0255%

Overall 0.022% 355/1,613,598 alleles · ultra-rare exomes 323/1,461,402 · genomes 32/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0291%	3,439
African / African-American	0.0107%	9,364
Remaining individualsnot grpmax-eligible	0.0048%	20,821
Finnishnot grpmax-eligible	0.00156%	64,028

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: NIT1
Protein: p.Arg243Trp
Coding: c.727C>T
MANE Select: NM_005600
dbSNP: rs144065383
Type: single nucleotide variant
Location: chr1:161120508 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.57
Residue 243: a UniProt-annotated variant site (in bsvd4; likely pathogenic; loss of protein abundance in homozygous patient cells; decreased function in metabolite repair); the cn hydrolase domain

Full NIT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

brain small vessel disease 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NIT1 p.Cys67_Ala68insTer Pathogenic ★ same condition
NIT1 c.591+2T>G Likely pathogenic ★ same type
DEDD p.Arg261Leu Uncertain significance ★ ⚠ same type
NIT1 p.Ala117Thr Uncertain significance ★ ⚠ same type
NIT1 p.Ala236Thr Uncertain significance ★ ⚠ same type
NIT1 p.Ala68Val Uncertain significance ★ ⚠ same type
NIT1 p.Ala74Pro Uncertain significance ★ ⚠ same type
NIT1 p.Ala79Gly 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/nit1-p-arg243trp (accessed [today's date]).

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