Is NPHP1 p.Met268Thr (c.803T>C) pathogenic?

NPHP1 p.Met268Thr (c.803T>C) is classified Conflicting classifications of pathogenicity in NPHP1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1443); Rare (popmax 0.345%, afr); Associated with nephronophthisis.

What condition is associated with NPHP1 p.Met268Thr (c.803T>C)?

NPHP1 p.Met268Thr (c.803T>C) is associated with nephronophthisis, nephronophthisis 1, Senior-Loken syndrome 1 (ClinVar).

How common is NPHP1 p.Met268Thr (c.803T>C) in the general population?

NPHP1 p.Met268Thr (c.803T>C) is rare (popmax 0.345%, 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 NPHP1 p.Met268Thr (c.803T>C)?

AlphaMissense predicts likely benign (score 0.1443) — an in-silico prediction, not a clinical call.

NPHP1 p.Met268Thr

c.803T>C · rs114250691 · VCV288369

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1443 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.345%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.1443	likely benign
REVEL	0.323	indeterminate
SaProt	LLR -5.18	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 9.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 81 kb · p 0.26 · regional, not allelic
Overall
CADD	18.55	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 M323T vs ClinVar M268T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.345% African / African-American · 259/75,062 alleles

Filtering AF 0.31% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.297%

Overall 0.0192% 309/1,613,540 alleles · rare exomes 149/1,461,214 · genomes 160/152,326 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.345%	290
Admixed American	0.0433%	2,308
Middle Eastern	0.033%	3,029
Remaining individualsnot grpmax-eligible	0.0224%	4,464
South Asian	0.0022%	45,530
European (non-Finnish)	0.000509%	196,572

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.Met268Thr
Coding: c.803T>C
MANE Select: NM_001128178
dbSNP: rs114250691
Type: single nucleotide variant
Location: chr2:110163104 (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

Also linked: nephronophthisis 1 Senior-Loken syndrome 1 Joubert syndrome with renal defect inherited retinal dystrophy

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP1 p.Met268Ile Uncertain significance ★ same residue
NPHP1 c.1083+1G>A Likely pathogenic ★★ same condition
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

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-met268thr (accessed [today's date]).

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