Is IGFALS p.Ala575= (c.1725G>T) pathogenic?

IGFALS p.Ala575= (c.1725G>T) is classified Likely benign in IGFALS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). Very rare (popmax 0.00338%, amr).

How common is IGFALS p.Ala575= (c.1725G>T) in the general population?

IGFALS p.Ala575= (c.1725G>T) is very rare (popmax 0.00338%, amr) (gnomAD).

IGFALS p.Ala575=

c.1725G>T · VCV3768291

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00338%, amr)

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 -2.1	GERP -4
Overall
CADD	0.544	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00338% Admixed American · 2/59,242 alleles

Filtering AF 0.00224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00199%

Overall 0.0113% 181/1,607,614 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.391%	256
Remaining individualsnot grpmax-eligible	0.045%	2,222
Admixed Americangrpmax	0.00338%	29,621
European (non-Finnish)	0.00306%	32,720

Ashkenazi Jewish 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.Ala575=
Coding: c.1725G>T
MANE Select: NM_004970
Type: single nucleotide variant
Location: chr16:1790693 (GRCh38)
Gene constraint: LOEUF 1.908 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 91.13 · 1 PDB
Residue 575: the lrrct domain; a disulfide bond

Full IGFALS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IGFALS p.Ala575Val Uncertain significance ★ ⚠ same residue
IGFALS p.Asn276Ser Likely pathogenic ★★ same type
IGFALS p.Ala147Thr Uncertain significance ★★ ⚠ same type
IGFALS p.Ala229Thr Uncertain significance ★★ ⚠ same type
IGFALS p.Ala258Val Uncertain significance ★★ ⚠ same type
IGFALS p.Ala551Thr Uncertain significance ★★ ⚠ same type
IGFALS p.Arg157His Uncertain significance ★★ ⚠ same type
IGFALS p.Arg306Gln Uncertain significance ★★ ⚠ same type

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-ala575 (accessed [today's date]).

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