Is NPHP4 p.Ser331Gly (c.991A>G) pathogenic?

NPHP4 p.Ser331Gly (c.991A>G) is classified Uncertain significance in NPHP4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-27). AlphaMissense: likely benign (0.0837); Very rare (popmax 0.0033%, sas); Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Ser331Gly (c.991A>G)?

NPHP4 p.Ser331Gly (c.991A>G) is associated with Inborn genetic diseases, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Ser331Gly (c.991A>G) in the general population?

NPHP4 p.Ser331Gly (c.991A>G) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about NPHP4 p.Ser331Gly (c.991A>G)?

AlphaMissense predicts likely benign (score 0.0837) — an in-silico prediction, not a clinical call.

NPHP4 p.Ser331Gly

c.991A>G · rs370582651 · VCV2520460

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0837 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0837	likely benign
REVEL	0.378	indeterminate
SaProt	LLR -6.85	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	24.8	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 0.0033% South Asian · 3/91,026 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000434% 7/1,612,144 alleles · very rare exomes 6/1,459,902 · genomes 1/152,242 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,342
European (non-Finnish)	0.000339%	294,572

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: NPHP4
Protein: p.Ser331Gly
Coding: c.991A>G
MANE Select: NM_015102
dbSNP: rs370582651
Type: single nucleotide variant
Location: chr1:5948071 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44

Full NPHP4 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

Also linked: nephronophthisis 4 Senior-Loken syndrome 4

Similar variants

NPHP4 p.Ser331Thr Uncertain significance ★ ⚠ same residue
NPHP4 c.2304+1G>A Pathogenic ★★ same condition
NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.2611+1G>C Pathogenic ★★ same condition
NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.3644+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.517+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.518-2A>G 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/nphp4-p-ser331gly (accessed [today's date]).

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