Is ALG2 c.348+49G>A pathogenic?

ALG2 c.348+49G>A is classified Likely benign in ALG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-12-24). Rare (popmax 0.334%, nfe).

How common is ALG2 c.348+49G>A in the general population?

ALG2 c.348+49G>A is rare (popmax 0.334%, nfe) (gnomAD).

ALG2 c.348+49G>A

rs370928507 · VCV1190659

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.334%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +49	near-intronic (+49 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.26
Non-coding constraint	Z -1.63	1 kb window · o/e 1.10 · regional · uncalibrated
Overall
CADD	8.012	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.334% European (non-Finnish) · 3,807/1,139,752 alleles

Filtering AF 0.325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.321%

Overall 0.306% 4,686/1,530,406 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.29%	77
European (non-Finnish)grpmax	0.334%	299
Remaining individualsnot grpmax-eligible	0.297%	337
Admixed American	0.063%	1,587
African / African-American	0.0535%	1,869
Middle Eastern	0.0369%	2,707
South Asian	0.0107%	9,304

Finnish 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: ALG2
Coding: c.348+49G>A
MANE Select: NM_033087
dbSNP: rs370928507
Type: single nucleotide variant
Location: chr9:99221498 (GRCh38)
Gene constraint: LOEUF 1.408 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.03

Full ALG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALG2 c.348+568G>A Uncertain significance ★★ same type
ALG2 p.Ala29Pro Uncertain significance ★★ ⚠ same type
ALG2 p.Ala36Val Uncertain significance ★★ ⚠ same type
ALG2 p.Ala71Gly Uncertain significance ★★ ⚠ same type
ALG2 p.Ala71Val Uncertain significance ★★ ⚠ same type
ALG2 p.Arg129Gln Uncertain significance ★★ ⚠ same type
ALG2 p.Arg130Gln Uncertain significance ★★ ⚠ same type
ALG2 p.Arg251His Uncertain significance ★★ ⚠ 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/alg2-c-348-plus-49g-a (accessed [today's date]).

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