Is IGFALS p.Pro33= (c.99G>A) pathogenic?

IGFALS p.Pro33= (c.99G>A) is classified Benign/Likely benign in IGFALS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-05). Rare (popmax 0.853%, afr); Associated with short stature due to primary acid-labile subunit deficiency.

What condition is associated with IGFALS p.Pro33= (c.99G>A)?

IGFALS p.Pro33= (c.99G>A) is associated with short stature due to primary acid-labile subunit deficiency (ClinVar).

How common is IGFALS p.Pro33= (c.99G>A) in the general population?

IGFALS p.Pro33= (c.99G>A) is rare (popmax 0.853%, afr) (gnomAD).

IGFALS p.Pro33=

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.99G>A · rs189350550 · VCV318268

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.853%, afr)

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 -9.4	GERP -3
Overall
CADD	2.225	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.853% African / African-American · 640/74,990 alleles

Filtering AF 0.799% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.777%

Overall 0.0581% 928/1,596,744 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.853%	117
Middle Eastern	0.101%	991
Admixed American	0.0953%	1,049
Remaining individualsnot grpmax-eligible	0.0821%	1,218
Ashkenazi Jewishnot grpmax-eligible	0.0509%	1,967
European (non-Finnish)	0.0126%	7,908
East Asian	0.00893%	11,198
Finnishnot grpmax-eligible	0.00808%	12,382
South Asian	0.0022%	45,433

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.Pro33=
Coding: c.99G>A
MANE Select: NM_004970
dbSNP: rs189350550
Type: single nucleotide variant
Location: chr16:1792319 (GRCh38)
Gene constraint: LOEUF 1.908 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 91.13 · 1 PDB
Residue 33: the lrrnt domain

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.Pro33Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-pro33 (accessed [today's date]).

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