Is NPHP1 p.Met1Thr (c.2T>C) pathogenic?

NPHP1 p.Met1Thr (c.2T>C) is classified Uncertain significance in NPHP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-11). Very rare (popmax 0.00329%, sas).

How common is NPHP1 p.Met1Thr (c.2T>C) in the general population?

NPHP1 p.Met1Thr (c.2T>C) is very rare (popmax 0.00329%, sas) (gnomAD).

NPHP1 p.Met1Thr

c.2T>C · rs2467622201 · VCV3063842

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.444	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 0.55, phastCons 1
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,086 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000248% 4/1,613,926 alleles · very rare exomes 4/1,461,624 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,362
European (non-Finnish)	8.48e-05%	1,179,885

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.Met1Thr
Coding: c.2T>C
MANE Select: NM_001128178
dbSNP: rs2467622201
Type: single nucleotide variant
Location: chr2:110204967 (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

Similar variants

NPHP1 p.Met1Ile Likely pathogenic ★ same residue
NPHP1 p.Met1Leu Likely pathogenic ★ same residue
NPHP1 c.1083+1G>A Likely pathogenic ★★ same type
NPHP1 c.1270-1G>A Pathogenic ★★ same type
NPHP1 c.1270-2A>G Pathogenic/Likely pathogenic ★★ same type
NPHP1 c.143+1G>C Likely pathogenic ★★ same type
NPHP1 c.144-1G>A Pathogenic/Likely pathogenic ★★ same type
NPHP1 c.1716+1G>T Pathogenic/Likely pathogenic ★★ same type

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-met1thr (accessed [today's date]).

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