Is NPHP3 p.Ser1314Thr (c.3941G>C) pathogenic?

NPHP3 p.Ser1314Thr (c.3941G>C) is classified Benign/Likely benign in NPHP3 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.0807); Low-frequency (popmax 2.16%, afr); Associated with nephronophthisis.

What condition is associated with NPHP3 p.Ser1314Thr (c.3941G>C)?

NPHP3 p.Ser1314Thr (c.3941G>C) is associated with nephronophthisis, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Ser1314Thr (c.3941G>C) in the general population?

NPHP3 p.Ser1314Thr (c.3941G>C) is low-frequency (popmax 2.16%, afr) (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 NPHP3 p.Ser1314Thr (c.3941G>C)?

AlphaMissense predicts likely benign (score 0.0807) — an in-silico prediction, not a clinical call.

NPHP3 p.Ser1314Thr

c.3941G>C · rs75316802 · VCV188351

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0807 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.16%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.0807	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -7.16	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 5.2	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 11 kb · p 0.0019 · regional, not allelic
Overall
CADD	19.46	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 2.16% African / African-American · 1,620/75,036 alleles

Filtering AF 2.07% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.04%

Overall 0.117% 1,886/1,614,114 alleles · low-frequency exomes 952/1,461,818 · genomes 934/152,296 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.16%	46
Admixed American	0.185%	541
Remaining individualsnot grpmax-eligible	0.174%	573
Middle Eastern	0.0825%	1,212
South Asian	0.00878%	11,385
European (non-Finnish)	0.0028%	35,757

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: NPHP3
Protein: p.Ser1314Thr
Coding: c.3941G>C
MANE Select: NM_153240
dbSNP: rs75316802
Type: single nucleotide variant
Location: chr3:132681962 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB
Residue 1314: the 'disordered' region; a UniProt-annotated variant site (in nphp3; likely benign)

Full NPHP3 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

Also linked: renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome nephronophthisis 3

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP3 c.1985+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP3 c.3201+1G>T Likely pathogenic ★★ same condition
NPHP3 c.393+1G>C Likely pathogenic ★★ same condition
NPHP3 c.520-1G>T Pathogenic ★★ same condition
NPHP3 c.823+1G>T Likely pathogenic ★★ same condition
NPHP3 c.958-2A>G Pathogenic ★★ same condition
NPHP3 p.Arg1125Ter Pathogenic ★★ same condition
NPHP3 p.Arg1259Ter Pathogenic/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/nphp3-p-ser1314thr (accessed [today's date]).

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