Is NIN p.Arg2052Ser (c.6156G>C) pathogenic?

NIN p.Arg2052Ser (c.6156G>C) is classified Uncertain significance in NIN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-29). AlphaMissense: ambiguous (0.5524); Ultra-rare (popmax 0.0357%, eas).

How common is NIN p.Arg2052Ser (c.6156G>C) in the general population?

NIN p.Arg2052Ser (c.6156G>C) is ultra-rare (popmax 0.0357%, eas) (gnomAD).

What do computational predictors say about NIN p.Arg2052Ser (c.6156G>C)?

AlphaMissense predicts ambiguous (score 0.5524) — an in-silico prediction, not a clinical call.

NIN p.Arg2052Ser

c.6156G>C · rs534805269 · VCV2349559

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5524 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, eas)

Computational evidence

Protein change
AlphaMissense	0.5524	ambiguous
REVEL	0.332	indeterminate
SaProt	LLR -5.45	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.8	GERP -3.6
Regional constraint	o/e 1.00	unconstrained · MANE · 48 kb · p 0.87 · regional, not allelic
Overall
CADD	12.62	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 0.0357% East Asian · 16/44,866 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.0128% 207/1,614,074 alleles · ultra-rare exomes 190/1,461,778 · genomes 17/152,296 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0357%	2,804
South Asian	0.0165%	6,072
African / African-American	0.0133%	7,504
Remaining individualsnot grpmax-eligible	0.0128%	7,813
European (non-Finnish)	0.0128%	7,814
Finnishnot grpmax-eligible	0.00937%	10,673
Admixed American	0.00167%	60,008

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: NIN
Protein: p.Arg2052Ser
Coding: c.6156G>C
MANE Select: NM_020921
dbSNP: rs534805269
Type: single nucleotide variant
Location: chr14:50725989 (GRCh38)
Gene constraint: LOEUF 0.62 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.47

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

Similar variants

NIN p.Arg2052Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
NIN p.Arg2052Thr Uncertain significance ★ ⚠ same residue
NIN p.Arg2039Ter Likely pathogenic ★★ same type
NIN p.Ala1049Thr Uncertain significance ★★ ⚠ same type
NIN p.Ala1212Val Uncertain significance ★★ ⚠ same type
NIN p.Ala1350Gly Uncertain significance ★★ ⚠ same type
NIN p.Ala1741Val Uncertain significance ★★ ⚠ same type
NIN p.Ala1755Thr 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/nin-p-arg2052ser (accessed [today's date]).

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