Is NPHP1 p.Thr267Met (c.800C>T) pathogenic?

NPHP1 p.Thr267Met (c.800C>T) is classified Likely benign in NPHP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.1064); Rare (popmax 0.134%, eas); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Thr267Met (c.800C>T)?

NPHP1 p.Thr267Met (c.800C>T) is associated with nephronophthisis (ClinVar).

How common is NPHP1 p.Thr267Met (c.800C>T) in the general population?

NPHP1 p.Thr267Met (c.800C>T) is rare (popmax 0.134%, eas) (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 NPHP1 p.Thr267Met (c.800C>T)?

AlphaMissense predicts likely benign (score 0.1064) — an in-silico prediction, not a clinical call.

NPHP1 p.Thr267Met

c.800C>T · rs141907218 · VCV1564712

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1064 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.134%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.1064	likely benign
REVEL	0.327	indeterminate
SaProt	LLR -6.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.29	acceptor loss, 25 bp away · masked 0 · deltas
Pangolin	Δ0.38	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.5	GERP -0.084, phastCons 0.073
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM T322M vs ClinVar T267M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.134% East Asian · 60/44,870 alleles

Filtering AF 0.107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0968%

Overall 0.00477% 77/1,613,142 alleles · rare exomes 62/1,460,896 · genomes 15/152,246 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.134%	748
Middle Eastern	0.0165%	6,058
South Asian	0.00439%	22,762
Admixed American	0.00167%	60,016
African / African-American	0.00133%	75,016
European (non-Finnish)	0.000848%	117,914

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: NPHP1
Protein: p.Thr267Met
Coding: c.800C>T
MANE Select: NM_001128178
dbSNP: rs141907218
Type: single nucleotide variant
Location: chr2:110163107 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.22 · 2 PDB

Full NPHP1 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

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP1 p.Thr267= Conflicting classifications of pathogenicity ★ same residue
NPHP1 c.1270-1G>A Pathogenic ★★ same condition
NPHP1 c.1270-2A>G Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.143+1G>C Likely pathogenic ★★ same condition
NPHP1 c.144-1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.1716+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.329+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP1 c.522+1G>A 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/nphp1-p-thr267met (accessed [today's date]).

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