Is TIAM1 p.Arg669Cys (c.2005C>T) pathogenic?

TIAM1 p.Arg669Cys (c.2005C>T) is classified Uncertain significance in TIAM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.8933); Very rare (popmax 0.00167%, amr).

How common is TIAM1 p.Arg669Cys (c.2005C>T) in the general population?

TIAM1 p.Arg669Cys (c.2005C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TIAM1 p.Arg669Cys (c.2005C>T)?

AlphaMissense predicts likely pathogenic (score 0.8933) — an in-silico prediction, not a clinical call.

TIAM1 p.Arg669Cys

c.2005C>T · VCV4184393

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8933 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8933	likely pathogenic
REVEL	0.351	indeterminate
SaProt	LLR -12.38	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 65 kb · p 7e-08 · regional, not allelic
Overall
CADD	27.8	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 0.00167% Admixed American · 1/59,928 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,613,054 alleles · very rare exomes 9/1,460,874 · genomes 0/152,180 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,928
European (non-Finnish)	0.000678%	147,437

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: TIAM1
Protein: p.Arg669Cys
Coding: c.2005C>T
MANE Select: NM_001353694
Type: single nucleotide variant
Location: chr21:31217690 (GRCh38)
Gene constraint: LOEUF 0.469 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 59.82 · 10 PDB

Full TIAM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TIAM1 p.Arg669His Uncertain significance ★ ⚠ same residue
TIAM1 p.Ala1004Thr Uncertain significance ★★ ⚠ same type
TIAM1 p.Ala549Val Uncertain significance ★★ ⚠ same type
TIAM1 p.Arg678His Uncertain significance ★★ ⚠ same type
TIAM1 p.Glu144Lys Uncertain significance ★★ ⚠ same type
TIAM1 p.Glu1567Asp Uncertain significance ★★ ⚠ same type
TIAM1 p.His1010Pro Uncertain significance ★★ ⚠ same type
TIAM1 p.Leu232Ser Uncertain significance ★★ ⚠ 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/tiam1-p-arg669cys (accessed [today's date]).

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