Is ALG1 p.Pro354His (c.1061C>A) pathogenic?

ALG1 p.Pro354His (c.1061C>A) is classified Uncertain significance in ALG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-11-13). AlphaMissense: likely pathogenic (0.6833); Very rare (popmax 0.000424%, nfe); Associated with congenital nephrotic syndrome, Finnish type.

What condition is associated with ALG1 p.Pro354His (c.1061C>A)?

ALG1 p.Pro354His (c.1061C>A) is associated with congenital nephrotic syndrome, Finnish type (ClinVar).

How common is ALG1 p.Pro354His (c.1061C>A) in the general population?

ALG1 p.Pro354His (c.1061C>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

How is Congenital nephrotic syndrome, Finnish type inherited?

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

What do computational predictors say about ALG1 p.Pro354His (c.1061C>A)?

AlphaMissense predicts likely pathogenic (score 0.6833) — an in-silico prediction, not a clinical call.

ALG1 p.Pro354His

c.1061C>A · rs549910242 · VCV1028631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6833 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital nephrotic syndrome, Finnish type

Computational evidence

Protein change
AlphaMissense	0.6833	likely pathogenic
REVEL	0.735	pathogenic-leaning
SaProt	LLR -15.89	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,690 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000415% 6/1,444,088 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,222
European (non-Finnish)grpmax	0.000424%	235,938

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ALG1
Protein: p.Pro354His
Coding: c.1061C>A
MANE Select: NM_019109
dbSNP: rs549910242
Type: single nucleotide variant
Location: chr16:5081045 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.24

Full ALG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital nephrotic syndrome, Finnish type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital nephrotic syndrome, Finnish type (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

ALG1 p.Pro354Arg Uncertain significance ★ ⚠ same residue
ALG1 p.Pro354Leu Uncertain significance ★ same residue
ALG1 p.Pro354Ser Uncertain significance ★ ⚠ same residue
ALG1 p.Pro354= Likely benign ★ same residue
ALG1 p.Ser258Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
ALG1 c.1187+1G>A Pathogenic/Likely pathogenic ★★ same type
ALG1 c.1187+2T>C Pathogenic ★★ same type
ALG1 c.1188-2A>G 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/alg1-p-pro354his (accessed [today's date]).

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