Is NIN p.His994Pro (c.2981A>C) pathogenic?

NIN p.His994Pro (c.2981A>C) is classified Uncertain significance in NIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: ambiguous (0.4002); Ultra-rare (popmax 0.0395%, sas).

How common is NIN p.His994Pro (c.2981A>C) in the general population?

NIN p.His994Pro (c.2981A>C) is ultra-rare (popmax 0.0395%, sas) (gnomAD).

What do computational predictors say about NIN p.His994Pro (c.2981A>C)?

AlphaMissense predicts ambiguous (score 0.4002) — an in-silico prediction, not a clinical call.

NIN p.His994Pro

c.2981A>C · VCV3919734

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4002 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4002	ambiguous
REVEL	0.203	benign-leaning
SaProt	LLR -14.30	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 48 kb · p 0.87 · regional, not allelic
Overall
CADD	23.1	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 0.0395% South Asian · 36/91,094 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.00266% 43/1,614,152 alleles · ultra-rare exomes 42/1,461,888 · genomes 1/152,264 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0395%	2,530
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.000424%	236,012

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.His994Pro
Coding: c.2981A>C
MANE Select: NM_020921
Type: single nucleotide variant
Location: chr14:50758049 (GRCh38)
Gene constraint: LOEUF 0.62 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.47
Residue 994: the 'important for interaction with cep170' region

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

Similar variants

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
NIN p.Ala1755Val Uncertain significance ★★ ⚠ same type
NIN p.Ala1813Gly 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-his994pro (accessed [today's date]).

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