Is ALG3 p.Arg277His (c.830G>A) pathogenic?

ALG3 p.Arg277His (c.830G>A) is classified Uncertain significance in ALG3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-08). AlphaMissense: ambiguous (0.3425); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with ALG3 p.Arg277His (c.830G>A)?

ALG3 p.Arg277His (c.830G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ALG3 p.Arg277His (c.830G>A) in the general population?

ALG3 p.Arg277His (c.830G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ALG3 p.Arg277His (c.830G>A)?

AlphaMissense predicts ambiguous (score 0.3425) — an in-silico prediction, not a clinical call.

ALG3 p.Arg277His

c.830G>A · VCV3852249

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3425 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3425	ambiguous
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -11.31	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 2,165 bp · p 0.0031 · regional, not allelic
Overall
CADD	32.0	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 · 1/75,004 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00123% 18/1,461,644 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-Americangrpmax	0.00133%	75,004
European (non-Finnish)	0.00127%	78,657
South Asian	0.0011%	91,080

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: ALG3
Protein: p.Arg277His
Coding: c.830G>A
MANE Select: NM_005787
Type: single nucleotide variant
Location: chr3:184243893 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALG3 p.Arg277Cys Uncertain significance ★ ⚠ same residue
ALG3 p.Ala102Ser Uncertain significance ★★ ⚠ same condition
ALG3 p.Arg229Cys Uncertain significance ★★ ⚠ same condition
ALG3 p.Arg27Gly Uncertain significance ★★ ⚠ same condition
ALG3 p.Arg378Cys Uncertain significance ★★ ⚠ same condition
ALG3 p.Asn83Ser Uncertain significance ★★ ⚠ same condition
ALG3 p.Cys21Gly Uncertain significance ★★ ⚠ same condition
ALG3 p.Cys21Phe 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/alg3-p-arg277his (accessed [today's date]).

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