Is IGFALS p.Arg548Trp (c.1642C>T) pathogenic?

IGFALS p.Arg548Trp (c.1642C>T) is classified Benign/Likely benign in IGFALS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-05-09). AlphaMissense: likely benign (0.1676); Common (popmax 26.1%, afr) — 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.Arg548Trp (c.1642C>T)?

IGFALS p.Arg548Trp (c.1642C>T) is associated with short stature due to primary acid-labile subunit deficiency (ClinVar).

What do computational predictors say about IGFALS p.Arg548Trp (c.1642C>T)?

AlphaMissense predicts likely benign (score 0.1676) — an in-silico prediction, not a clinical call.

IGFALS p.Arg548Trp

Q: How common is IGFALS p.Arg548Trp (c.1642C>T) in the general population?

IGFALS p.Arg548Trp (c.1642C>T) is common (popmax 26.1%, afr) — 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.1642C>T · rs9282731 · VCV318235

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1676 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 26.1%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

short stature due to primary acid-labile subunit deficiency

Computational evidence

Protein change
AlphaMissense	0.1676	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -10.68	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3	GERP -4.4
Regional constraint	o/e 1.17	unconstrained · MANE · 3,049 bp · p 4.3e-07 · regional, not allelic
Overall
CADD	1.948	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 26.1% African / African-American · 19,355/74,266 alleles

Filtering AF 25.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 25.6%

Overall 1.86% 29,429/1,583,154 alleles · common exomes 17,881/1,430,892 · genomes 11,548/152,262 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	26.1%	4
South Asian	7.42%	13
Remaining individualsnot grpmax-eligible	2.52%	40
Admixed American	1.84%	54
Middle Eastern	1.68%	59
Ashkenazi Jewishnot grpmax-eligible	0.107%	936
East Asian	0.0956%	1,046
European (non-Finnish)	0.0756%	1,322

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.Arg548Trp
Coding: c.1642C>T
MANE Select: NM_004970
dbSNP: rs9282731
Type: single nucleotide variant
Location: chr16:1790776 (GRCh38)
Gene constraint: LOEUF 1.908 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 91.13 · 1 PDB
Residue 548: the lrrct domain; a UniProt-annotated variant site (in)

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.Arg548Gln 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
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-arg548trp (accessed [today's date]).

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