Is NIT1 p.Ser231Cys (c.692C>G) pathogenic?

NIT1 p.Ser231Cys (c.692C>G) is classified Uncertain significance in NIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: likely benign (0.0853); Ultra-rare (popmax 0.0593%, nfe).

How common is NIT1 p.Ser231Cys (c.692C>G) in the general population?

NIT1 p.Ser231Cys (c.692C>G) is ultra-rare (popmax 0.0593%, nfe) (gnomAD).

What do computational predictors say about NIT1 p.Ser231Cys (c.692C>G)?

AlphaMissense predicts likely benign (score 0.0853) — an in-silico prediction, not a clinical call.

NIT1 p.Ser231Cys

c.692C>G · rs144821669 · VCV2350387

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0853 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0853	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -5.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.096	GERP -0.65, phastCons 0.001
Regional constraint	o/e 1.07	unconstrained · MANE · 2,585 bp · p 0.18 · regional, not allelic
Overall
CADD	16.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0593% European (non-Finnish) · 700/1,180,004 alleles

Filtering AF 0.0557% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.0483% 780/1,614,072 alleles · ultra-rare exomes 735/1,461,824 · genomes 45/152,248 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0593%	1,686
Admixed American	0.0566%	1,765
Remaining individualsnot grpmax-eligible	0.0304%	3,290
Finnishnot grpmax-eligible	0.0265%	3,767
Middle Eastern	0.0166%	6,034
African / African-American	0.0107%	9,376
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Ser231Cys
Coding: c.692C>G
MANE Select: NM_005600
dbSNP: rs144821669
Type: single nucleotide variant
Location: chr1:161120207 (GRCh38)
Gene constraint: LOEUF 1.044 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.57
Residue 231: the cn hydrolase domain

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

Similar variants

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
NIT1 p.Arg207Gln 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-ser231cys (accessed [today's date]).

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