Is ITGAM p.Arg688His (c.2063G>A) pathogenic?

ITGAM p.Arg688His (c.2063G>A) is classified Uncertain significance in ITGAM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-25). AlphaMissense: ambiguous (0.4049); Very rare (popmax 0.00193%, amr).

How common is ITGAM p.Arg688His (c.2063G>A) in the general population?

ITGAM p.Arg688His (c.2063G>A) is very rare (popmax 0.00193%, amr) (gnomAD).

What do computational predictors say about ITGAM p.Arg688His (c.2063G>A)?

AlphaMissense predicts ambiguous (score 0.4049) — an in-silico prediction, not a clinical call.

ITGAM p.Arg688His

c.2063G>A · rs771862568 · VCV2994460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4049 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00193%, amr)

Computational evidence

Protein change
AlphaMissense	0.4049	ambiguous
REVEL	0.464	indeterminate
SaProt	LLR -12.68	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP -2.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 72 kb · p 0.00026 · regional, not allelic
Overall
CADD	21.5	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 0.00193% Admixed American · 1/51,902 alleles

Filtering AF 0.000367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000266%

Overall 0.000767% 12/1,563,584 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00193%	51,902
Remaining individualsnot grpmax-eligible	0.00165%	60,706
South Asian	0.00118%	84,800
European (non-Finnish)	0.00078%	128,283

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.Arg688His
Coding: c.2063G>A
MANE Select: NM_000632
dbSNP: rs771862568
Type: single nucleotide variant
Location: chr16:31324459 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.30 · 31 PDB
Residue 688: a disulfide bond

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

Similar variants

ITGAM p.Arg688Cys 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-arg688his (accessed [today's date]).

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