Is ALG5 p.Arg208His (c.623G>A) pathogenic?

ALG5 p.Arg208His (c.623G>A) is classified Pathogenic in ALG5 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2022-10-04). AlphaMissense: likely pathogenic (0.8133); Very rare (popmax 0.00111%, sas); Associated with polycystic kidney disease 7.

What condition is associated with ALG5 p.Arg208His (c.623G>A)?

ALG5 p.Arg208His (c.623G>A) is associated with polycystic kidney disease 7 (ClinVar).

How common is ALG5 p.Arg208His (c.623G>A) in the general population?

ALG5 p.Arg208His (c.623G>A) is very rare (popmax 0.00111%, sas) (gnomAD).

How is Autosomal dominant polycystic kidney disease inherited?

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

What do computational predictors say about ALG5 p.Arg208His (c.623G>A)?

AlphaMissense predicts likely pathogenic (score 0.8133) — an in-silico prediction, not a clinical call.

ALG5 p.Arg208His

c.623G>A · rs749484470 · VCV1708164

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8133 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

polycystic kidney disease 7

Computational evidence

Protein change
AlphaMissense	0.8133	likely pathogenic ✓ concordant with ClinVar
REVEL	0.535	indeterminate
SaProt	LLR -15.09	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 49 kb · p 9.9e-06 · regional, not allelic
Overall
CADD	34.0	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 0.00111% South Asian · 1/90,082 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000311% 5/1,606,566 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	90,082
European (non-Finnish)	0.00034%	294,456

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: ALG5
Protein: p.Arg208His
Coding: c.623G>A
MANE Select: NM_013338
dbSNP: rs749484470
Type: single nucleotide variant
Location: chr13:36965725 (GRCh38)
Gene constraint: LOEUF 0.823 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 92.29
Residue 208: a UniProt-annotated variant site (in pkd7; loss of function in protein n-linked glycosylation; unable to rescue defective pkd1 glycosylation and maturation in alg5-deficient cells)

Full ALG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

polycystic kidney disease 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant polycystic kidney disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ALG5 p.Thr249Met Uncertain significance ★★ ⚠ same condition
ALG5 c.239-2A>G Likely pathogenic ★ same condition
ALG5 p.Arg39Ter Likely pathogenic ★ same condition
ALG5 p.Arg97Ter Pathogenic ★ same condition
ALG5 p.Trp224Ter Likely pathogenic ★ same condition
ALG5 p.Arg309Ter Uncertain significance ★ same condition
ALG5 p.Gln235His Uncertain significance ★ ⚠ same condition
ALG5 p.Gln235Leu Uncertain significance ★ ⚠ 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/alg5-p-arg208his (accessed [today's date]).

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