Is IGFALS p.Pro287= (c.861C>T) pathogenic?

IGFALS p.Pro287= (c.861C>T) is classified Conflicting classifications of pathogenicity in IGFALS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2018-04-06). Ultra-rare (popmax 0.0567%, sas); Associated with short stature due to primary acid-labile subunit deficiency.

What condition is associated with IGFALS p.Pro287= (c.861C>T)?

IGFALS p.Pro287= (c.861C>T) is associated with short stature due to primary acid-labile subunit deficiency (ClinVar).

How common is IGFALS p.Pro287= (c.861C>T) in the general population?

IGFALS p.Pro287= (c.861C>T) is ultra-rare (popmax 0.0567%, sas) (gnomAD).

IGFALS p.Pro287=

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.861C>T · rs750405773 · VCV318250

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0567%, sas)

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 -20	GERP -5.1
Overall
CADD	0.034	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0567% South Asian · 49/86,460 alleles

Filtering AF 0.044% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0395%

Overall 0.00547% 86/1,570,854 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0567%	1,764
Admixed American	0.0318%	3,145
East Asian	0.00952%	10,503
Remaining individualsnot grpmax-eligible	0.0082%	12,190
Ashkenazi Jewishnot grpmax-eligible	0.00346%	28,912
African / African-American	0.00135%	73,868
European (non-Finnish)	0.000776%	128,879

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.Pro287=
Coding: c.861C>T
MANE Select: NM_004970
dbSNP: rs750405773
Type: single nucleotide variant
Location: chr16:1791557 (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.Pro287Leu 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-pro287 (accessed [today's date]).

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