Is ALG1 p.Arg247His (c.740G>A) pathogenic?

ALG1 p.Arg247His (c.740G>A) is classified Likely pathogenic in ALG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). AlphaMissense: likely benign (0.0686); Very rare (popmax 0.00267%, afr); Associated with ALG1-related disorder.

What condition is associated with ALG1 p.Arg247His (c.740G>A)?

ALG1 p.Arg247His (c.740G>A) is associated with ALG1-related disorder (ClinVar).

How common is ALG1 p.Arg247His (c.740G>A) in the general population?

ALG1 p.Arg247His (c.740G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ALG1 p.Arg247His (c.740G>A)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

ALG1 p.Arg247His

c.740G>A · VCV4928446

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALG1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign ⚠ discordant with ClinVar
REVEL	0.097	moderately benign-leaning
SaProt	LLR -6.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	donor loss · deltas
Pangolin	Δ0.71	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.1	GERP -0.48, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	25.1	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 0.00267% African / African-American · 2/74,850 alleles

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

Overall 0.00119% 19/1,598,138 alleles · very rare exomes 18/1,445,964 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,425
Finnishnot grpmax-eligible	0.00198%	50,486
European (non-Finnish)	0.00127%	78,652
South Asian	0.0011%	90,992

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.Arg247His
Coding: c.740G>A
MANE Select: NM_019109
Type: single nucleotide variant
Location: chr16:5078017 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.24
Residue 247: the 'disordered' region

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

Disease context

ALG1-related disorder

Similar variants

ALG1 p.Arg247Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ALG1 p.Arg247Leu Uncertain significance ★ ⚠ same residue
ALG1 p.Ser258Leu Pathogenic/Likely pathogenic ★★ same condition
ALG1 p.Tyr113Ter Pathogenic/Likely pathogenic ★★ same condition
ALG1 p.Arg247fs Pathogenic ★ same residue
ALG1 c.1187+3A>G Conflicting classifications of pathogenicity ★ same condition
ALG1 c.*5T>C Likely benign same condition
ALG1 p.Cys390= Likely benign 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/alg1-p-arg247his (accessed [today's date]).

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