Is ITGAM p.Arg519His (c.1556G>A) pathogenic?

ITGAM p.Arg519His (c.1556G>A) is classified Uncertain significance in ITGAM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-07). AlphaMissense: likely benign (0.1115); Very rare (popmax 0.00881%, sas).

How common is ITGAM p.Arg519His (c.1556G>A) in the general population?

ITGAM p.Arg519His (c.1556G>A) is very rare (popmax 0.00881%, sas) (gnomAD).

What do computational predictors say about ITGAM p.Arg519His (c.1556G>A)?

AlphaMissense predicts likely benign (score 0.1115) — an in-silico prediction, not a clinical call.

ITGAM p.Arg519His

c.1556G>A · rs370878031 · VCV2991811

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1115 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00881%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1115	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -11.25	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 72 kb · p 0.00026 · regional, not allelic
Overall
CADD	26.5	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 0.00881% South Asian · 8/90,830 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.00168% 27/1,609,538 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00881%	11,354
African / African-American	0.00536%	18,661
East Asian	0.00223%	44,852
Remaining individualsnot grpmax-eligible	0.00161%	62,236
European (non-Finnish)	0.0011%	90,658

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.Arg519His
Coding: c.1556G>A
MANE Select: NM_000632
dbSNP: rs370878031
Type: single nucleotide variant
Location: chr16:31297803 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.30 · 31 PDB
Residue 519: a β-strand

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

Similar variants

ITGAM p.Arg519Cys Uncertain significance ★ ⚠ same residue
ITGAM p.Arg519= Likely benign ★ 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

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-arg519his (accessed [today's date]).

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