Is GIT1 p.Arg43Cys (c.127C>T) pathogenic?

GIT1 p.Arg43Cys (c.127C>T) is classified Uncertain significance in GIT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely pathogenic (0.9495); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with GIT1 p.Arg43Cys (c.127C>T)?

GIT1 p.Arg43Cys (c.127C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GIT1 p.Arg43Cys (c.127C>T) in the general population?

GIT1 p.Arg43Cys (c.127C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about GIT1 p.Arg43Cys (c.127C>T)?

AlphaMissense predicts likely pathogenic (score 0.9495) — an in-silico prediction, not a clinical call.

GIT1 p.Arg43Cys

c.127C>T · VCV4029858

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9495 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9495	likely pathogenic
REVEL	0.424	indeterminate
SaProt	LLR -11.96	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 12 kb · p 1.9e-17 · regional, not allelic
Overall
CADD	33.0	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 0.00267% African / African-American · 2/75,012 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000744% 12/1,612,122 alleles · very rare exomes 9/1,459,840 · genomes 3/152,282 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,506
East Asian	0.00223%	44,878
South Asian	0.0022%	45,494
Remaining individualsnot grpmax-eligible	0.0016%	62,456
European (non-Finnish)	0.000509%	196,642

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.Arg43Cys
Coding: c.127C>T
MANE Select: NM_014030
Type: single nucleotide variant
Location: chr17:29583542 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.72
Residue 43: the arf-gap domain; the 'interaction with gamma-tubulin and localization to the centrosome' 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 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
GIT1 p.Ala488Val 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-arg43cys (accessed [today's date]).

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