Is NIT1 p.Arg315Ser (c.945G>T) pathogenic?

NIT1 p.Arg315Ser (c.945G>T) is classified Uncertain significance in NIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: likely pathogenic (0.9573); Very rare (popmax 0.00458%, nfe).

How common is NIT1 p.Arg315Ser (c.945G>T) in the general population?

NIT1 p.Arg315Ser (c.945G>T) is very rare (popmax 0.00458%, nfe) (gnomAD).

What do computational predictors say about NIT1 p.Arg315Ser (c.945G>T)?

AlphaMissense predicts likely pathogenic (score 0.9573) — an in-silico prediction, not a clinical call.

NIT1 p.Arg315Ser

c.945G>T · rs765742286 · VCV2226614

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9573 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00458%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9573	likely pathogenic · top 5% in NIT1
REVEL	0.637	indeterminate
SaProt	LLR -15.04	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 1.8	GERP 0.52, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 2,585 bp · p 0.18 · regional, not allelic
Overall
CADD	23.9	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 0.00458% European (non-Finnish) · 54/1,180,052 alleles

Filtering AF 0.00358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00341% 55/1,613,696 alleles · very rare exomes 52/1,461,510 · genomes 3/152,186 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00458%	21,853
Admixed American	0.00167%	60,004

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.Arg315Ser
Coding: c.945G>T
MANE Select: NM_005600
dbSNP: rs765742286
Type: single nucleotide variant
Location: chr1:161120726 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.57

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

Similar variants

NIT1 p.Arg315Gly Uncertain significance ★ ⚠ same residue
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-arg315ser (accessed [today's date]).

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