Is IGFALS p.Phe602Cys (c.1805T>G) pathogenic?

IGFALS p.Phe602Cys (c.1805T>G) is classified Likely pathogenic in IGFALS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-21). AlphaMissense: likely pathogenic (0.9387); Very rare (popmax 0.00473%, eas); Associated with IGFALS-related disorder.

What condition is associated with IGFALS p.Phe602Cys (c.1805T>G)?

IGFALS p.Phe602Cys (c.1805T>G) is associated with IGFALS-related disorder (ClinVar).

How common is IGFALS p.Phe602Cys (c.1805T>G) in the general population?

IGFALS p.Phe602Cys (c.1805T>G) is very rare (popmax 0.00473%, eas) (gnomAD).

What do computational predictors say about IGFALS p.Phe602Cys (c.1805T>G)?

AlphaMissense predicts likely pathogenic (score 0.9387) — an in-silico prediction, not a clinical call.

IGFALS p.Phe602Cys

c.1805T>G · VCV4927378

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9387 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00473%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

IGFALS-related disorder

Computational evidence

Protein change
AlphaMissense	0.9387	likely pathogenic ✓ concordant with ClinVar · top 7% in IGFALS
REVEL	0.413	indeterminate
SaProt	LLR -14.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 3,049 bp · p 4.3e-07 · regional, not allelic
Overall
CADD	24.6	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 0.00473% East Asian · 2/42,246 alleles

Filtering AF 0.000785% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000294%

Overall 0.000212% 3/1,416,852 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00473%	21,123
Remaining individualsnot grpmax-eligible	0.00164%	60,864

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.Phe602Cys
Coding: c.1805T>G
MANE Select: NM_004970
Type: single nucleotide variant
Location: chr16:1790613 (GRCh38)
Gene constraint: LOEUF 1.908 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 91.13 · 1 PDB
Residue 602: the lrrct domain; a disulfide bond

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

Disease context

IGFALS-related disorder

Similar variants

IGFALS p.Phe602= Likely benign ★ same residue
IGFALS p.Leu134Gln Pathogenic ★ same condition
IGFALS p.Asn492Ser Uncertain significance ★ same condition
IGFALS p.Pro73Leu Conflicting classifications of pathogenicity ★ ⚠ same condition
IGFALS c.17-52C>T Benign same condition
IGFALS p.Asp51= Likely benign same condition
IGFALS p.Gln482= Likely benign same condition
IGFALS p.Glu35fs Pathogenic/Likely pathogenic ★★ 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-phe602cys (accessed [today's date]).

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