Is ALG5 p.Arg155Gln (c.464G>A) pathogenic?

ALG5 p.Arg155Gln (c.464G>A) is classified Uncertain significance in ALG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-08). AlphaMissense: likely benign (0.1705); Ultra-rare (popmax 0.0826%, mid).

How common is ALG5 p.Arg155Gln (c.464G>A) in the general population?

ALG5 p.Arg155Gln (c.464G>A) is ultra-rare (popmax 0.0826%, mid) (gnomAD).

What do computational predictors say about ALG5 p.Arg155Gln (c.464G>A)?

AlphaMissense predicts likely benign (score 0.1705) — an in-silico prediction, not a clinical call.

ALG5 p.Arg155Gln

c.464G>A · VCV3852259

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1705 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0826%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1705	likely benign
REVEL	0.466	indeterminate
SaProt	LLR -9.67	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 49 kb · p 9.9e-06 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0826% Middle Eastern · 5/6,052 alleles

Filtering AF 0.0536% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0487%

Overall 0.0102% 165/1,612,606 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.439%	228
Ashkenazi Jewishnot grpmax-eligible	0.105%	954
Middle Easterngrpmax	0.0826%	1,210
South Asian	0.0671%	1,490
Remaining individualsnot grpmax-eligible	0.0176%	5,678
European (non-Finnish)	0.00449%	22,251

Amish 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: ALG5
Protein: p.Arg155Gln
Coding: c.464G>A
MANE Select: NM_013338
Type: single nucleotide variant
Location: chr13:36985724 (GRCh38)
Gene constraint: LOEUF 0.823 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 92.29

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

Similar variants

ALG5 p.Thr249Met Uncertain significance ★★ ⚠ same type
ALG5 c.239-2A>G Likely pathogenic ★ same type
ALG5 p.Arg39Ter Likely pathogenic ★ same type
ALG5 p.Arg97Ter Pathogenic ★ same type
ALG5 p.Trp224Ter Likely pathogenic ★ same type
ALG5 p.Ala14Thr Uncertain significance ★ ⚠ same type
ALG5 p.Ala16Ser Uncertain significance ★ ⚠ same type
ALG5 p.Ala17Val Uncertain significance ★ ⚠ 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/alg5-p-arg155gln (accessed [today's date]).

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