Is IGF1 c.402+1663C>A pathogenic?

IGF1 c.402+1663C>A is classified Likely benign in IGF1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-18). AlphaMissense: likely benign (0.0925); Low-frequency (popmax 2.99%, afr).

How common is IGF1 c.402+1663C>A in the general population?

IGF1 c.402+1663C>A is low-frequency (popmax 2.99%, afr) (gnomAD).

What do computational predictors say about IGF1 c.402+1663C>A?

AlphaMissense predicts likely benign (score 0.0925) — an in-silico prediction, not a clinical call.

IGF1 c.402+1663C>A

rs6213 · VCV376935

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0925 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.99%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0925	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -7.46	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
Splice region	donor +1663	deep intronic (+1663 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -1.5, phastCons 1
Non-coding constraint	Z 0.17	1 kb window · o/e 0.99 · regional · uncalibrated
Overall
CADD	18.26	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 2.99% African / African-American · 2,241/74,938 alleles

Filtering AF 2.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.85%

Overall 0.163% 2,633/1,613,700 alleles · low-frequency exomes 1,352/1,461,592 · genomes 1,281/152,108 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.99%	33
Middle Eastern	0.396%	253
Remaining individualsnot grpmax-eligible	0.219%	456
Admixed American	0.143%	698
European (non-Finnish)	0.0119%	8,427
South Asian	0.00549%	18,208

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: IGF1
Coding: c.402+1663C>A
MANE Select: NM_000618
dbSNP: rs6213
Type: single nucleotide variant
Location: chr12:102417846 (GRCh38)
Gene constraint: LOEUF 0.675 · pLI 0.76 (gnomAD)
Structure: AlphaFold pLDDT 59.69 · 32 PDB

Full IGF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IGF1 c.*260A>T Uncertain significance ★★ same type
IGF1 p.Ala115Val Uncertain significance ★★ ⚠ same type
IGF1 p.Arg119His Uncertain significance ★★ ⚠ same type
IGF1 p.Arg122His Uncertain significance ★★ ⚠ same type
IGF1 p.Cys54Trp Uncertain significance ★★ ⚠ same type
IGF1 p.Leu7Phe Uncertain significance ★★ ⚠ same type
IGF1 c.*105T>C Likely benign ★★ same type
IGF1 c.*1770C>T Benign ★★ 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/igf1-c-402-plus-1663c-a (accessed [today's date]).

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