Is NPHP1 p.Gly112Glu (c.335G>A) pathogenic?

NPHP1 p.Gly112Glu (c.335G>A) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-18). AlphaMissense: likely benign (0.0712); Ultra-rare (popmax 0.0132%, sas); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Gly112Glu (c.335G>A)?

NPHP1 p.Gly112Glu (c.335G>A) is associated with nephronophthisis (ClinVar).

How common is NPHP1 p.Gly112Glu (c.335G>A) in the general population?

NPHP1 p.Gly112Glu (c.335G>A) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about NPHP1 p.Gly112Glu (c.335G>A)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

NPHP1 p.Gly112Glu

c.335G>A · rs1434802962 · VCV1928412

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -4.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.29	acceptor loss, 3 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -1.2	GERP -2.8
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	0.297	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% South Asian · 12/91,058 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.000744% 12/1,612,816 alleles · ultra-rare exomes 11/1,460,748 · genomes 1/152,068 · joint denominator

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: NPHP1
Protein: p.Gly112Glu
Coding: c.335G>A
MANE Select: NM_001128178
dbSNP: rs1434802962
Type: single nucleotide variant
Location: chr2:110169993 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB
Residue 112: the 'disordered' region

Full NPHP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

NPHP1 p.Gly112= Conflicting classifications of pathogenicity ★ same residue
NPHP1 c.1270-1G>A Pathogenic ★★ same condition
NPHP1 c.1270-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.143+1G>C Likely pathogenic ★★ same condition
NPHP1 c.144-1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.1716+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.329+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.522+1G>A Likely pathogenic ★★ 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/nphp1-p-gly112glu (accessed [today's date]).

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