Is NIN p.Pro1111Ala (c.3331C>G) pathogenic?

NIN p.Pro1111Ala (c.3331C>G) is classified Benign in NIN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0646); Common (popmax 25.4%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Seckel syndrome 7.

What condition is associated with NIN p.Pro1111Ala (c.3331C>G)?

NIN p.Pro1111Ala (c.3331C>G) is associated with Seckel syndrome 7 (ClinVar).

What do computational predictors say about NIN p.Pro1111Ala (c.3331C>G)?

AlphaMissense predicts likely benign (score 0.0646) — an in-silico prediction, not a clinical call.

NIN p.Pro1111Ala

Q: How common is NIN p.Pro1111Ala (c.3331C>G) in the general population?

NIN p.Pro1111Ala (c.3331C>G) is common (popmax 25.4%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3331C>G · rs2236316 · VCV129787

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0646 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 25.4%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Seckel syndrome 7

Computational evidence

Protein change
AlphaMissense	0.0646	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -5.61	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 1.4	GERP -3.7, phastCons 0.86
Regional constraint	o/e 1.00	unconstrained · MANE · 48 kb · p 0.87 · regional, not allelic
Overall
CADD	1.709	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 25.4% South Asian · 23,126/91,072 alleles

Filtering AF 25.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 25.3%

Overall 24.1% 388,636/1,613,862 alleles · common exomes 357,643/1,461,784 · genomes 30,993/152,078 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	25.4%	4
European (non-Finnish)	25.4%	4
Middle Eastern	24.2%	4
Ashkenazi Jewishnot grpmax-eligible	24.2%	4
Remaining individualsnot grpmax-eligible	23.5%	4
Admixed American	23.2%	4
Amishnot grpmax-eligible	22.6%	4
Finnishnot grpmax-eligible	20.9%	5
East Asian	17.2%	6
African / African-American	9.98%	10

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.Pro1111Ala
Coding: c.3331C>G
MANE Select: NM_020921
dbSNP: rs2236316
Type: single nucleotide variant
Location: chr14:50757699 (GRCh38)
Gene constraint: LOEUF 0.62 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.47
Residue 1111: a UniProt-annotated variant site (in); the 'important for interaction with cep170' region; the 'interacts with dsp' region

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.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
NIN c.5628+5T>C Benign ★★ same condition
NIN c.6192+12C>T 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-pro1111ala (accessed [today's date]).

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