Is IGFALS p.Thr522= (c.1566G>A) pathogenic?

IGFALS p.Thr522= (c.1566G>A) is classified Benign in IGFALS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-11). Common (popmax 10.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with short stature due to primary acid-labile subunit deficiency.

What condition is associated with IGFALS p.Thr522= (c.1566G>A)?

IGFALS p.Thr522= (c.1566G>A) is associated with short stature due to primary acid-labile subunit deficiency (ClinVar).

IGFALS p.Thr522=

Q: How common is IGFALS p.Thr522= (c.1566G>A) in the general population?

IGFALS p.Thr522= (c.1566G>A) is common (popmax 10.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Short stature due to primary acid-labile subunit deficiency inherited?

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

c.1566G>A · rs2230053 · VCV318236

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 10.4%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

short stature due to primary acid-labile subunit deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.49	GERP -1.2
Overall
CADD	5.89	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.4% East Asian · 4,379/41,978 alleles

Filtering AF 10.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.1%

Overall 0.882% 13,807/1,565,800 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	10.4%	10
Ashkenazi Jewishnot grpmax-eligible	7.46%	13
Remaining individualsnot grpmax-eligible	1.89%	53
South Asian	1.73%	58
Middle Eastern	0.885%	113
African / African-American	0.784%	128
European (non-Finnish)	0.318%	314
Admixed American	0.317%	315
Finnishnot grpmax-eligible	0.29%	345

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: IGFALS
Protein: p.Thr522=
Coding: c.1566G>A
MANE Select: NM_004970
dbSNP: rs2230053
Type: single nucleotide variant
Location: chr16:1790852 (GRCh38)
Gene constraint: LOEUF 1.908 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 91.13 · 1 PDB

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

Disease context

short stature due to primary acid-labile subunit deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Short stature due to primary acid-labile subunit deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

IGFALS p.Asn276Ser Likely pathogenic ★★ same condition
IGFALS p.Ala147Thr Uncertain significance ★★ ⚠ same condition
IGFALS p.Ala258Val Uncertain significance ★★ ⚠ same condition
IGFALS p.Ala551Thr Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg306Gln Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg493His Uncertain significance ★★ ⚠ same condition
IGFALS p.Asp52Asn Uncertain significance ★★ ⚠ same condition
IGFALS p.Asp570Asn 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/igfals-p-thr522 (accessed [today's date]).

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