Is NPHP4 p.Ser856Cys (c.2566A>T) pathogenic?

NPHP4 p.Ser856Cys (c.2566A>T) is classified Uncertain significance in NPHP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: likely benign (0.0742); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with NPHP4 p.Ser856Cys (c.2566A>T)?

NPHP4 p.Ser856Cys (c.2566A>T) is associated with Inborn genetic diseases (ClinVar).

How common is NPHP4 p.Ser856Cys (c.2566A>T) in the general population?

NPHP4 p.Ser856Cys (c.2566A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NPHP4 p.Ser856Cys (c.2566A>T)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

NPHP4 p.Ser856Cys

c.2566A>T · VCV3407383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -10.56	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.2	GERP -3.8
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	4.78	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NPHP4
Protein: p.Ser856Cys
Coding: c.2566A>T
MANE Select: NM_015102
Type: single nucleotide variant
Location: chr1:5880159 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 856: the 'sufficient for basal bodies localization' region

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

Similar variants

NPHP4 p.Ala1220Val Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala1263Gly Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala649Asp Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala678Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala956Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Ala988Thr Uncertain significance ★★ ⚠ same condition
NPHP4 p.Arg1109Gln Uncertain significance ★★ ⚠ same condition
NPHP4 p.Arg1135Cys 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/nphp4-p-ser856cys (accessed [today's date]).

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