Is NPHP4 p.Ala171Thr (c.511G>A) pathogenic?

NPHP4 p.Ala171Thr (c.511G>A) is classified Benign/Likely benign in NPHP4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.0772); Low-frequency (popmax 1.28%, afr); Associated with nephronophthisis.

What condition is associated with NPHP4 p.Ala171Thr (c.511G>A)?

NPHP4 p.Ala171Thr (c.511G>A) is associated with nephronophthisis (ClinVar).

How common is NPHP4 p.Ala171Thr (c.511G>A) in the general population?

NPHP4 p.Ala171Thr (c.511G>A) is low-frequency (popmax 1.28%, 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 NPHP4 p.Ala171Thr (c.511G>A)?

AlphaMissense predicts likely benign (score 0.0772) — an in-silico prediction, not a clinical call.

NPHP4 p.Ala171Thr

c.511G>A · rs113765431 · VCV235474

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0772 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.28%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis

Computational evidence

Protein change
AlphaMissense	0.0772	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.7	GERP -4.2
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	8.377	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.28% African / African-American · 957/74,910 alleles

Filtering AF 1.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.18%

Overall 0.0736% 1,180/1,602,564 alleles · low-frequency exomes 597/1,450,228 · genomes 583/152,336 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.28%	78
Remaining individualsnot grpmax-eligible	0.179%	559
Middle Eastern	0.0993%	1,007
Admixed American	0.0941%	1,063
South Asian	0.017%	5,887
European (non-Finnish)	0.00298%	33,573
East Asian	0.00225%	44,442

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.Ala171Thr
Coding: c.511G>A
MANE Select: NM_015102
dbSNP: rs113765431
Type: single nucleotide variant
Location: chr1:5967305 (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

For Nephronophthisis (Orphanet):

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

Similar variants

NPHP4 p.Ala171Val Uncertain significance ★★ ⚠ same residue
NPHP4 p.Ala171Ser Uncertain significance ★ ⚠ 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.518-2A>G 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-ala171thr (accessed [today's date]).

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