Is ALG3 p.Arg266His (c.797G>A) pathogenic?

ALG3 p.Arg266His (c.797G>A) is classified Uncertain significance in ALG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-22). AlphaMissense: ambiguous (0.5467); Very rare (popmax 0.00133%, afr).

How common is ALG3 p.Arg266His (c.797G>A) in the general population?

ALG3 p.Arg266His (c.797G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ALG3 p.Arg266His (c.797G>A)?

AlphaMissense predicts ambiguous (score 0.5467) — an in-silico prediction, not a clinical call.

ALG3 p.Arg266His

c.797G>A · rs780902065 · VCV1678059

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5467 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5467	ambiguous
REVEL	0.959	strongly pathogenic-leaning
SaProt	LLR -10.99	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 2,165 bp · p 0.0031 · regional, not allelic
Overall
CADD	33.0	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 0.00133% African / African-American · 1/74,938 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,613,798 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,938
South Asian	0.0011%	91,092
European (non-Finnish)	0.00017%	589,950

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: ALG3
Protein: p.Arg266His
Coding: c.797G>A
MANE Select: NM_005787
dbSNP: rs780902065
Type: single nucleotide variant
Location: chr3:184243926 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.05

Full ALG3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALG3 p.Arg266Cys Pathogenic ★★ same residue
ALG3 c.444+1G>T Likely pathogenic ★★ same type
ALG3 p.Arg171Gln Pathogenic/Likely pathogenic ★★ same type
ALG3 p.Arg354Cys Likely pathogenic ★★ same type
ALG3 p.Arg354His Pathogenic/Likely pathogenic ★★ same type
ALG3 p.Asn174Ser Likely pathogenic ★★ ⚠ same type
ALG3 p.Gly55= Pathogenic/Likely pathogenic ★★ same type
ALG3 p.Ile69Thr 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/alg3-p-arg266his (accessed [today's date]).

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