Is IGFALS p.Arg413Cys (c.1237C>T) pathogenic?

IGFALS p.Arg413Cys (c.1237C>T) is classified Uncertain significance in IGFALS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: ambiguous (0.4208); Very rare (popmax 0.005%, amr); Associated with Inborn genetic diseases.

What condition is associated with IGFALS p.Arg413Cys (c.1237C>T)?

IGFALS p.Arg413Cys (c.1237C>T) is associated with Inborn genetic diseases (ClinVar).

How common is IGFALS p.Arg413Cys (c.1237C>T) in the general population?

IGFALS p.Arg413Cys (c.1237C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about IGFALS p.Arg413Cys (c.1237C>T)?

AlphaMissense predicts ambiguous (score 0.4208) — an in-silico prediction, not a clinical call.

IGFALS p.Arg413Cys

c.1237C>T · VCV4621995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4208 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4208	ambiguous
REVEL	0.469	indeterminate
SaProt	LLR -13.32	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 0.071, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 3,049 bp · p 4.3e-07 · regional, not allelic
Overall
CADD	28.3	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 0.005% Admixed American · 3/59,988 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000933% 15/1,607,250 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,996
African / African-American	0.00267%	37,457
European (non-Finnish)	0.000848%	117,988

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.Arg413Cys
Coding: c.1237C>T
MANE Select: NM_004970
Type: single nucleotide variant
Location: chr16:1791181 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IGFALS p.Arg413His Uncertain significance ★ ⚠ same residue
IGFALS p.Ala229Thr Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg157His Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg308His Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg332His Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg375Trp Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg402His Uncertain significance ★★ ⚠ same condition
IGFALS p.Arg467Cys 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-arg413cys (accessed [today's date]).

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