Is NRIP1 p.Ser436Phe (c.1307C>T) pathogenic?

NRIP1 p.Ser436Phe (c.1307C>T) is classified Uncertain significance in NRIP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-21). AlphaMissense: likely pathogenic (0.8551); Rare (popmax 0.13%, amr); Associated with Inborn genetic diseases.

What condition is associated with NRIP1 p.Ser436Phe (c.1307C>T)?

NRIP1 p.Ser436Phe (c.1307C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NRIP1 p.Ser436Phe (c.1307C>T) in the general population?

NRIP1 p.Ser436Phe (c.1307C>T) is rare (popmax 0.13%, amr) (gnomAD).

What do computational predictors say about NRIP1 p.Ser436Phe (c.1307C>T)?

AlphaMissense predicts likely pathogenic (score 0.8551) — an in-silico prediction, not a clinical call.

NRIP1 p.Ser436Phe

c.1307C>T · rs767528211 · VCV1376370

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8551 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.13%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8551	likely pathogenic · top 9% in NRIP1
REVEL	0.244	benign-leaning
SaProt	LLR -8.69	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,473 bp · p 0.013 · regional, not allelic
Overall
CADD	23.7	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 0.13% Admixed American · 78/60,004 alleles

Filtering AF 0.107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0982%

Overall 0.00539% 87/1,614,018 alleles · rare exomes 72/1,461,780 · genomes 15/152,238 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.13%	769
South Asian	0.00549%	18,216
Remaining individualsnot grpmax-eligible	0.0032%	31,252
European (non-Finnish)	0.000169%	589,977

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: NRIP1
Protein: p.Ser436Phe
Coding: c.1307C>T
MANE Select: NM_003489
dbSNP: rs767528211
Type: single nucleotide variant
Location: chr21:14966886 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 46.10 · 17 PDB
Residue 436: the 'repression domain 2' region; the 'required for targeting to small nuclear foci' region

Full NRIP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NRIP1 p.Ser436= Likely benign ★ same residue
NRIP1 p.Ala1096Gly Uncertain significance ★★ ⚠ same condition
NRIP1 p.Ala360Ser Uncertain significance ★★ ⚠ same condition
NRIP1 p.Ala36Pro Uncertain significance ★★ ⚠ same condition
NRIP1 p.Ala792Val Uncertain significance ★★ ⚠ same condition
NRIP1 p.Arg1082Gly Uncertain significance ★★ ⚠ same condition
NRIP1 p.Arg98Trp Uncertain significance ★★ ⚠ same condition
NRIP1 p.Asn45Asp Uncertain significance ★★ ⚠ 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/nrip1-p-ser436phe (accessed [today's date]).

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