Is ITGAM p.Arg684Cys (c.2050C>T) pathogenic?

ITGAM p.Arg684Cys (c.2050C>T) is classified Uncertain significance in ITGAM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: ambiguous (0.3606); Very rare (popmax 0.00226%, nfe).

How common is ITGAM p.Arg684Cys (c.2050C>T) in the general population?

ITGAM p.Arg684Cys (c.2050C>T) is very rare (popmax 0.00226%, nfe) (gnomAD).

What do computational predictors say about ITGAM p.Arg684Cys (c.2050C>T)?

AlphaMissense predicts ambiguous (score 0.3606) — an in-silico prediction, not a clinical call.

ITGAM p.Arg684Cys

c.2050C>T · rs1409315332 · VCV2905856

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3606 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00226%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3606	ambiguous
REVEL	0.226	benign-leaning
SaProt	LLR -14.00	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 2.2, phastCons 0.7
Regional constraint	o/e 0.91	unconstrained · MANE · 72 kb · p 0.00026 · regional, not allelic
Overall
CADD	22.2	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 0.00226% European (non-Finnish) · 26/1,150,408 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00173% 27/1,556,972 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00226%	44,246
African / African-American	0.00136%	73,316

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: ITGAM
Protein: p.Arg684Cys
Coding: c.2050C>T
MANE Select: NM_000632
dbSNP: rs1409315332
Type: single nucleotide variant
Location: chr16:31324446 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.30 · 31 PDB
Residue 684: a β-strand; a disulfide bond

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

Similar variants

ITGAM p.Arg684His Uncertain significance ★ ⚠ same residue
ITGAM c.704+5G>A Uncertain significance ★★ same type
ITGAM p.Ala31Thr Uncertain significance ★★ ⚠ same type
ITGAM p.Ala433Val Uncertain significance ★★ ⚠ same type
ITGAM p.Ala753Val Uncertain significance ★★ ⚠ same type
ITGAM p.Ala943Val Uncertain significance ★★ ⚠ same type
ITGAM p.Arg1003His Uncertain significance ★★ ⚠ same type
ITGAM p.Arg131Trp 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/itgam-p-arg684cys (accessed [today's date]).

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