Is IGFALS p.Pro259= (c.777G>A) pathogenic?

IGFALS p.Pro259= (c.777G>A) is classified Conflicting classifications of pathogenicity in IGFALS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-05). Ultra-rare (popmax 0.0392%, nfe); Associated with short stature due to primary acid-labile subunit deficiency.

What condition is associated with IGFALS p.Pro259= (c.777G>A)?

IGFALS p.Pro259= (c.777G>A) is associated with short stature due to primary acid-labile subunit deficiency (ClinVar).

How common is IGFALS p.Pro259= (c.777G>A) in the general population?

IGFALS p.Pro259= (c.777G>A) is ultra-rare (popmax 0.0392%, nfe) (gnomAD).

IGFALS p.Pro259=

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.777G>A · rs376070681 · VCV318253

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 0.0392%, nfe)

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 -8.7	GERP -5.1
Overall
CADD	0.885	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0392% European (non-Finnish) · 457/1,164,724 alleles

Filtering AF 0.0362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0351%

Overall 0.0308% 486/1,578,278 alleles · ultra-rare exomes 459/1,426,052 · genomes 27/152,226 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0392%	2,549
Remaining individualsnot grpmax-eligible	0.0229%	4,367
African / African-American	0.0162%	6,176
East Asian	0.00234%	42,808
Finnishnot grpmax-eligible	0.00174%	57,402
South Asian	0.00115%	87,030

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.Pro259=
Coding: c.777G>A
MANE Select: NM_004970
dbSNP: rs376070681
Type: single nucleotide variant
Location: chr16:1791641 (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.Pro259Leu Uncertain significance ★★ ⚠ same residue
IGFALS p.Pro259Thr Uncertain significance ★ ⚠ 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

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-pro259 (accessed [today's date]).

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