Is NIN p.Pro1971Gln (c.5912C>A) pathogenic?

NIN p.Pro1971Gln (c.5912C>A) is classified Conflicting classifications of pathogenicity in NIN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-02). AlphaMissense: likely benign (0.1061); Ultra-rare (popmax 0.0175%, mid); Associated with Seckel syndrome 7.

What condition is associated with NIN p.Pro1971Gln (c.5912C>A)?

NIN p.Pro1971Gln (c.5912C>A) is associated with Seckel syndrome 7 (ClinVar).

How common is NIN p.Pro1971Gln (c.5912C>A) in the general population?

NIN p.Pro1971Gln (c.5912C>A) is ultra-rare (popmax 0.0175%, mid) (gnomAD).

What do computational predictors say about NIN p.Pro1971Gln (c.5912C>A)?

AlphaMissense predicts likely benign (score 0.1061) — an in-silico prediction, not a clinical call.

NIN p.Pro1971Gln

c.5912C>A · rs200441923 · VCV734344

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1061 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Seckel syndrome 7

Computational evidence

Protein change
AlphaMissense	0.1061	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -6.54	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 9.9	GERP 1.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 48 kb · p 0.87 · regional, not allelic
Overall
CADD	19.96	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 0.0175% Middle Eastern · 1/5,708 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.0512% 825/1,612,054 alleles · ultra-rare exomes 698/1,459,748 · genomes 127/152,306 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.947%	106
Remaining individualsnot grpmax-eligible	0.0881%	1,135
Middle Easterngrpmax	0.0175%	5,708
European (non-Finnish)	0.0133%	7,510
East Asian	0.0111%	8,969
African / African-American	0.00133%	75,016

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1971Gln
Coding: c.5912C>A
MANE Select: NM_020921
dbSNP: rs200441923
Type: single nucleotide variant
Location: chr14:50729689 (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

Disease context

Seckel syndrome 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NIN p.Pro1971= Likely benign ★★ same residue
NIN p.Pro1971Leu Uncertain significance ★ ⚠ same residue
NIN p.Arg2039Ter Likely pathogenic ★★ same condition
NIN p.Ser1009Asn Uncertain significance ★★ ⚠ same condition
NIN p.Thr2092Ile Uncertain significance ★★ same condition
NIN p.Val117Met Uncertain significance ★★ ⚠ same condition
NIN p.Val1768Phe Uncertain significance ★★ ⚠ same condition
NIN c.1775-26G>C Benign ★★ same condition

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-pro1971gln (accessed [today's date]).

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