Is ALG6 p.Val238Ile (c.712G>A) pathogenic?

ALG6 p.Val238Ile (c.712G>A) is classified Uncertain significance in ALG6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-03). AlphaMissense: likely benign (0.1535); Ultra-rare (popmax 0.0417%, amr); Associated with ALG6-congenital disorder of glycosylation 1C.

What condition is associated with ALG6 p.Val238Ile (c.712G>A)?

ALG6 p.Val238Ile (c.712G>A) is associated with ALG6-congenital disorder of glycosylation 1C (ClinVar).

How common is ALG6 p.Val238Ile (c.712G>A) in the general population?

ALG6 p.Val238Ile (c.712G>A) is ultra-rare (popmax 0.0417%, amr) (gnomAD).

How is ALG6-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ALG6 p.Val238Ile (c.712G>A)?

AlphaMissense predicts likely benign (score 0.1535) — an in-silico prediction, not a clinical call.

ALG6 p.Val238Ile

c.712G>A · rs769947380 · VCV2169240

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1535 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ALG6-congenital disorder of glycosylation 1C

Computational evidence

Protein change
AlphaMissense	0.1535	likely benign
REVEL	0.575	indeterminate
SaProt	LLR -9.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 66 kb · p 0.00074 · regional, not allelic
Overall
CADD	25.9	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 0.0417% Admixed American · 25/59,996 alleles

Filtering AF 0.0289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0247%

Overall 0.00161% 26/1,613,930 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0417%	2,400
South Asian	0.0011%	91,082

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: ALG6
Protein: p.Val238Ile
Coding: c.712G>A
MANE Select: NM_013339
dbSNP: rs769947380
Type: single nucleotide variant
Location: chr1:63411957 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.08

Full ALG6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALG6-congenital disorder of glycosylation 1C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For ALG6-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ALG6 p.Val238= Likely benign ★ same residue
ALG6 p.Val238Phe Uncertain significance ★ ⚠ same residue
ALG6 c.1128-1G>A Likely pathogenic ★★ same condition
ALG6 c.1128-2A>C Likely pathogenic ★★ same condition
ALG6 c.1326+1G>A Pathogenic/Likely pathogenic ★★ same condition
ALG6 c.257+5G>A Pathogenic/Likely pathogenic ★★ same condition
ALG6 c.429+1G>T Likely pathogenic ★★ same condition
ALG6 c.495-2A>G Likely pathogenic ★★ 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/alg6-p-val238ile (accessed [today's date]).

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