Is NPHP4 p.Pro677= (c.2031C>T) pathogenic?

NPHP4 p.Pro677= (c.2031C>T) is classified Benign in NPHP4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Low-frequency (popmax 3.45%, afr); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Pro677= (c.2031C>T)?

NPHP4 p.Pro677= (c.2031C>T) is associated with nephronophthisis, nephronophthisis 4, Senior-Loken syndrome 4 (ClinVar).

How common is NPHP4 p.Pro677= (c.2031C>T) in the general population?

NPHP4 p.Pro677= (c.2031C>T) is low-frequency (popmax 3.45%, afr) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Pro677=

c.2031C>T · rs34373111 · VCV240966

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.45%, afr)

Conditions

nephronophthisis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.43 · evaluated, not missing
Constraint at this position
Conservation	phyloP -5.4	GERP -3.3
Overall
CADD	0.57	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.45% African / African-American · 2,592/75,038 alleles

Filtering AF 3.34% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.3%

Overall 0.193% 3,107/1,613,998 alleles · low-frequency exomes 1,566/1,461,694 · genomes 1,541/152,304 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.45%	29
Middle Eastern	0.363%	276
Remaining individualsnot grpmax-eligible	0.344%	291
Admixed American	0.257%	390
South Asian	0.0176%	5,693
Finnishnot grpmax-eligible	0.0109%	9,144
European (non-Finnish)	0.00831%	12,040
East Asian	0.00446%	22,442
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602

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.Pro677=
Coding: c.2031C>T
MANE Select: NM_015102
dbSNP: rs34373111
Type: single nucleotide variant
Location: chr1:5904729 (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

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

Also linked: nephronophthisis 4 Senior-Loken syndrome 4

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP4 p.Pro677Leu Uncertain significance ★ ⚠ same residue
NPHP4 p.Pro677Ser Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro677 (accessed [today's date]).

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