Is IGFALS p.Pro73Leu (c.218C>T) pathogenic?

IGFALS p.Pro73Leu (c.218C>T) is classified Conflicting classifications of pathogenicity in IGFALS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-09). AlphaMissense: likely benign (0.2701); Ultra-rare (popmax 0.011%, sas); Associated with IGFALS-related disorder.

What condition is associated with IGFALS p.Pro73Leu (c.218C>T)?

IGFALS p.Pro73Leu (c.218C>T) is associated with IGFALS-related disorder (ClinVar).

How common is IGFALS p.Pro73Leu (c.218C>T) in the general population?

IGFALS p.Pro73Leu (c.218C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about IGFALS p.Pro73Leu (c.218C>T)?

AlphaMissense predicts likely benign (score 0.2701) — an in-silico prediction, not a clinical call.

IGFALS p.Pro73Leu

c.218C>T · VCV3907274

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2701 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

IGFALS-related disorder

Computational evidence

Protein change
AlphaMissense	0.2701	likely benign
REVEL	0.798	moderately pathogenic-leaning
SaProt	LLR -11.69	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 3,049 bp · p 4.3e-07 · regional, not allelic
Overall
CADD	23.5	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 0.011% South Asian · 10/90,998 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00454%

Overall 0.00224% 36/1,610,272 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,922
South Asiangrpmax	0.011%	9,100
Remaining individualsnot grpmax-eligible	0.00481%	20,804
European (non-Finnish)	0.00136%	73,732
African / African-American	0.00133%	74,924

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.Pro73Leu
Coding: c.218C>T
MANE Select: NM_004970
Type: single nucleotide variant
Location: chr16:1792200 (GRCh38)
Gene constraint: LOEUF 1.908 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 91.13 · 1 PDB
Residue 73: the lrrnt domain; a UniProt-annotated variant site (in aclsd)

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

Disease context

IGFALS-related disorder

Similar variants

IGFALS p.Leu134Gln Pathogenic ★ same condition
IGFALS p.Phe602Cys Likely pathogenic ★ same condition
IGFALS p.Asn492Ser Uncertain significance ★ 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
IGFALS p.Ala92fs 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-pro73leu (accessed [today's date]).

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