Is IGFALS p.Leu97Phe (c.289C>T) pathogenic?

IGFALS p.Leu97Phe (c.289C>T) is classified Benign in IGFALS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2021-01-20). AlphaMissense: likely benign (0.2349); Low-frequency (popmax 4.1%, eas); Associated with short stature due to primary acid-labile subunit deficiency.

What condition is associated with IGFALS p.Leu97Phe (c.289C>T)?

IGFALS p.Leu97Phe (c.289C>T) is associated with short stature due to primary acid-labile subunit deficiency (ClinVar).

How common is IGFALS p.Leu97Phe (c.289C>T) in the general population?

IGFALS p.Leu97Phe (c.289C>T) is low-frequency (popmax 4.1%, eas) (gnomAD).

What do computational predictors say about IGFALS p.Leu97Phe (c.289C>T)?

AlphaMissense predicts likely benign (score 0.2349) — an in-silico prediction, not a clinical call.

IGFALS p.Leu97Phe

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.289C>T · rs35947557 · VCV318262

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2349 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.1%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

short stature due to primary acid-labile subunit deficiency

Computational evidence

Protein change
AlphaMissense	0.2349	likely benign
REVEL	0.409	indeterminate
SaProt	LLR -8.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 3,049 bp · p 4.3e-07 · regional, not allelic
Overall
CADD	22.6	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 4.1% East Asian · 1,837/44,824 alleles

Filtering AF 3.94% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.88%

Overall 0.131% 2,108/1,611,552 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	4.1%	24
Remaining individualsnot grpmax-eligible	0.354%	282
Admixed American	0.0184%	5,447
Middle Eastern	0.0165%	6,058
South Asian	0.0099%	10,100
African / African-American	0.00799%	12,508
European (non-Finnish)	0.00195%	51,290

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.Leu97Phe
Coding: c.289C>T
MANE Select: NM_004970
dbSNP: rs35947557
Type: single nucleotide variant
Location: chr16:1792129 (GRCh38)
Gene constraint: LOEUF 1.908 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 91.13 · 1 PDB
Residue 97: 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.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
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-leu97phe (accessed [today's date]).

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