Is IGF1R p.Cys1237Ser (c.3709T>A) pathogenic?

IGF1R p.Cys1237Ser (c.3709T>A) is classified Uncertain significance in IGF1R (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-17). AlphaMissense: likely pathogenic (0.9278); Ultra-rare (popmax 0.0467%, amr); Associated with Inborn genetic diseases.

What condition is associated with IGF1R p.Cys1237Ser (c.3709T>A)?

IGF1R p.Cys1237Ser (c.3709T>A) is associated with Inborn genetic diseases (ClinVar).

How common is IGF1R p.Cys1237Ser (c.3709T>A) in the general population?

IGF1R p.Cys1237Ser (c.3709T>A) is ultra-rare (popmax 0.0467%, amr) (gnomAD).

What do computational predictors say about IGF1R p.Cys1237Ser (c.3709T>A)?

AlphaMissense predicts likely pathogenic (score 0.9278) — an in-silico prediction, not a clinical call.

IGF1R p.Cys1237Ser

c.3709T>A · rs757046261 · VCV2159416

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9278 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9278	likely pathogenic
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -10.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 8,758 bp · p 0.028 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0467% Admixed American · 28/60,016 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0286%

Overall 0.0018% 29/1,614,038 alleles · ultra-rare exomes 27/1,461,852 · genomes 2/152,186 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0467%	2,143
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: IGF1R
Protein: p.Cys1237Ser
Coding: c.3709T>A
MANE Select: NM_000875
dbSNP: rs757046261
Type: single nucleotide variant
Location: chr15:98948695 (GRCh38)
Gene constraint: LOEUF 0.393 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 46 PDB
Residue 1237: the protein kinase domain

Full IGF1R 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

IGF1R p.Cys307Ter Pathogenic ★★ same condition
IGF1R p.Ala241Val Uncertain significance ★★ ⚠ same condition
IGF1R p.Ala263Val Uncertain significance ★★ ⚠ same condition
IGF1R p.Arg1223His Uncertain significance ★★ ⚠ same condition
IGF1R p.Arg1275Gln Uncertain significance ★★ ⚠ same condition
IGF1R p.Arg391Cys Uncertain significance ★★ ⚠ same condition
IGF1R p.Arg739Gln Uncertain significance ★★ ⚠ same condition
IGF1R p.Arg794Trp 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/igf1r-p-cys1237ser (accessed [today's date]).

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