Is GIT1 p.Arg409Trp (c.1225C>T) pathogenic?

GIT1 p.Arg409Trp (c.1225C>T) is classified Uncertain significance in GIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-02). AlphaMissense: ambiguous (0.4144); Very rare (popmax 0.00115%, sas); Associated with Inborn genetic diseases.

What condition is associated with GIT1 p.Arg409Trp (c.1225C>T)?

GIT1 p.Arg409Trp (c.1225C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GIT1 p.Arg409Trp (c.1225C>T) in the general population?

GIT1 p.Arg409Trp (c.1225C>T) is very rare (popmax 0.00115%, sas) (gnomAD).

What do computational predictors say about GIT1 p.Arg409Trp (c.1225C>T)?

AlphaMissense predicts ambiguous (score 0.4144) — an in-silico prediction, not a clinical call.

GIT1 p.Arg409Trp

c.1225C>T · VCV3854033

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4144 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00115%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4144	ambiguous
REVEL	0.424	indeterminate
SaProt	LLR -8.73	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP -1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 1,519 bp · p 0.045 · regional, not allelic
Overall
CADD	26.3	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 0.00115% South Asian · 1/87,222 alleles

Filtering AF 0.000126% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.000381% 6/1,575,020 alleles · very rare exomes 4/1,422,796 · genomes 2/152,224 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00115%	87,222
European (non-Finnish)	0.00043%	232,409

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: GIT1
Protein: p.Arg409Trp
Coding: c.1225C>T
MANE Select: NM_014030
Type: single nucleotide variant
Location: chr17:29576865 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.72
Residue 409: the 'disordered' region; the 'interaction with nck2 and grin3a' region; the 'required for localization at synapses' region; the 'interaction with ptk2/fak1' region

Full GIT1 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

GIT1 p.Arg409Gln Uncertain significance ★ ⚠ same residue
GIT1 c.762-205C>T Uncertain significance ★ same condition
GIT1 p.Ala130Thr Uncertain significance ★ ⚠ same condition
GIT1 p.Ala183Gly Uncertain significance ★ same condition
GIT1 p.Ala311Val Uncertain significance ★ ⚠ same condition
GIT1 p.Ala402Thr Uncertain significance ★ ⚠ same condition
GIT1 p.Ala466Val Uncertain significance ★ ⚠ same condition
GIT1 p.Ala488Thr 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/git1-p-arg409trp (accessed [today's date]).

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