Is ALG1 p.Asp412His (c.1234G>C) pathogenic?

ALG1 p.Asp412His (c.1234G>C) is classified Uncertain significance in ALG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-24). AlphaMissense: likely benign (0.2536); Very rare (popmax 8.48e-05%, nfe).

How common is ALG1 p.Asp412His (c.1234G>C) in the general population?

ALG1 p.Asp412His (c.1234G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ALG1 p.Asp412His (c.1234G>C)?

AlphaMissense predicts likely benign (score 0.2536) — an in-silico prediction, not a clinical call.

ALG1 p.Asp412His

c.1234G>C · rs200353530 · VCV1312250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2536	likely benign
REVEL	0.685	pathogenic-leaning
SaProt	LLR -7.06	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 0.31, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 13 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	25.0	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 8.48e-05% European (non-Finnish) · 1/1,179,784 alleles

Overall 6.92e-05% 1/1,446,012 alleles · very rare

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.Asp412His
Coding: c.1234G>C
MANE Select: NM_019109
dbSNP: rs200353530
Type: single nucleotide variant
Location: chr16:5083728 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.24

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

Similar variants

ALG1 p.Asp412Asn Uncertain significance ★★ ⚠ same residue
ALG1 p.Asp412= Likely benign ★ same residue
ALG1 c.1187+1G>A Pathogenic/Likely pathogenic ★★ same type
ALG1 c.1187+2T>C Pathogenic ★★ same type
ALG1 c.1188-2A>G Pathogenic/Likely pathogenic ★★ same type
ALG1 c.209-2A>G Likely pathogenic ★★ same type
ALG1 c.539+1G>A Pathogenic/Likely pathogenic ★★ same type
ALG1 c.630-2A>G 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/alg1-p-asp412his (accessed [today's date]).

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