Is IGFALS p.Arg306Gln (c.917G>A) pathogenic?

IGFALS p.Arg306Gln (c.917G>A) is classified Uncertain significance in IGFALS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-08). AlphaMissense: likely benign (0.0967); Rare (popmax 0.117%, eas); Associated with short stature due to primary acid-labile subunit deficiency.

What condition is associated with IGFALS p.Arg306Gln (c.917G>A)?

IGFALS p.Arg306Gln (c.917G>A) is associated with short stature due to primary acid-labile subunit deficiency (ClinVar).

How common is IGFALS p.Arg306Gln (c.917G>A) in the general population?

IGFALS p.Arg306Gln (c.917G>A) is rare (popmax 0.117%, eas) (gnomAD).

What do computational predictors say about IGFALS p.Arg306Gln (c.917G>A)?

AlphaMissense predicts likely benign (score 0.0967) — an in-silico prediction, not a clinical call.

IGFALS p.Arg306Gln

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.917G>A · rs201176815 · VCV318248

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0967 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.117%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

short stature due to primary acid-labile subunit deficiency

Computational evidence

Protein change
AlphaMissense	0.0967	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -6.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.5, phastCons 0.98
Regional constraint	o/e 1.17	unconstrained · MANE · 3,049 bp · p 4.3e-07 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.117% East Asian · 52/44,560 alleles

Filtering AF 0.0914% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0823%

Overall 0.00889% 143/1,607,982 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.117%	857
Finnishnot grpmax-eligible	0.00806%	12,400
South Asian	0.00774%	12,914
Remaining individualsnot grpmax-eligible	0.00643%	15,557
European (non-Finnish)	0.00637%	15,706

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.Arg306Gln
Coding: c.917G>A
MANE Select: NM_004970
dbSNP: rs201176815
Type: single nucleotide variant
Location: chr16:1791501 (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.Arg306Trp 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.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-arg306gln (accessed [today's date]).

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