Is NPHP4 p.Thr977= (c.2931G>A) pathogenic?

NPHP4 p.Thr977= (c.2931G>A) is classified Conflicting classifications of pathogenicity in NPHP4 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-09). Ultra-rare (popmax 0.0264%, sas); Associated with nephronophthisis 4.

What condition is associated with NPHP4 p.Thr977= (c.2931G>A)?

NPHP4 p.Thr977= (c.2931G>A) is associated with nephronophthisis 4, Senior-Loken syndrome 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Thr977= (c.2931G>A) in the general population?

NPHP4 p.Thr977= (c.2931G>A) is ultra-rare (popmax 0.0264%, sas) (gnomAD).

How is Nephronophthisis inherited?

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

NPHP4 p.Thr977=

c.2931G>A · rs756370084 · VCV595894

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0264%, sas)

Conditions

nephronophthisis 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -3.2
Overall
CADD	3.698	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0264% South Asian · 24/91,078 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.0109% 175/1,612,534 alleles · ultra-rare exomes 164/1,460,350 · genomes 11/152,184 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0264%	3,795
East Asian	0.0134%	7,482
Admixed American	0.0133%	7,501
European (non-Finnish)	0.0111%	9,007
Finnishnot grpmax-eligible	0.00478%	20,904
African / African-American	0.00267%	37,460
Remaining individualsnot grpmax-eligible	0.0016%	62,452

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.Thr977=
Coding: c.2931G>A
MANE Select: NM_015102
dbSNP: rs756370084
Type: single nucleotide variant
Location: chr1:5874987 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 977: the 'sufficient for basal bodies localization' region

Full NPHP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Senior-Loken syndrome 4 nephronophthisis

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP4 p.Thr977Ala Uncertain significance ★ ⚠ same residue
NPHP4 p.Thr977Met 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-thr977 (accessed [today's date]).

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