Is IGFALS p.Asp70= (c.210T>C) pathogenic?

IGFALS p.Asp70= (c.210T>C) is classified Benign in IGFALS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-05-08). Common (popmax 84.9%, mid) — 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.Asp70= (c.210T>C)?

IGFALS p.Asp70= (c.210T>C) is associated with short stature due to primary acid-labile subunit deficiency (ClinVar).

IGFALS p.Asp70=

Q: How common is IGFALS p.Asp70= (c.210T>C) in the general population?

IGFALS p.Asp70= (c.210T>C) is common (popmax 84.9%, mid) — 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.210T>C · rs3751893 · VCV318265

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 84.9%, mid) — too common for a highly-penetrant pathogenic allele

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 -12	GERP -5.1
Overall
CADD	0.015	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 84.9% Middle Eastern · 5,141/6,058 alleles

Filtering AF 82.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 82.3%

Overall 80.8% 1,300,002/1,608,936 alleles · common exomes 1,177,070/1,456,676 · genomes 122,932/152,260 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	88.7%	1
Middle Easterngrpmax	84.9%	1
Ashkenazi Jewishnot grpmax-eligible	84.8%	1
African / African-American	83.1%	1
European (non-Finnish)	81.9%	1
Admixed American	81%	1
Remaining individualsnot grpmax-eligible	80.4%	1
South Asian	75%	1
Finnishnot grpmax-eligible	71.9%	1
East Asian	69.7%	1

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp70=
Coding: c.210T>C
MANE Select: NM_004970
dbSNP: rs3751893
Type: single nucleotide variant
Location: chr16:1792208 (GRCh38)
Gene constraint: LOEUF 1.908 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 91.13 · 1 PDB
Residue 70: the lrrnt domain

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.Asp70Asn 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-asp70 (accessed [today's date]).

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