Is ITGAM p.Arg699Cys (c.2095C>T) pathogenic?

ITGAM p.Arg699Cys (c.2095C>T) is classified Uncertain significance in ITGAM (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-16). AlphaMissense: likely benign (0.1312); Ultra-rare (popmax 0.0534%, sas).

How common is ITGAM p.Arg699Cys (c.2095C>T) in the general population?

ITGAM p.Arg699Cys (c.2095C>T) is ultra-rare (popmax 0.0534%, sas) (gnomAD).

What do computational predictors say about ITGAM p.Arg699Cys (c.2095C>T)?

AlphaMissense predicts likely benign (score 0.1312) — an in-silico prediction, not a clinical call.

ITGAM p.Arg699Cys

c.2095C>T · rs538515225 · VCV1430703

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1312 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0534%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1312	likely benign
REVEL	0.01	strongly benign-leaning
SaProt	LLR -9.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -4.4
Regional constraint	o/e 0.91	unconstrained · MANE · 72 kb · p 0.00026 · regional, not allelic
Overall
CADD	15.24	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0534% South Asian · 47/88,036 alleles

Filtering AF 0.0412% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0369%

Overall 0.0244% 389/1,597,082 alleles · ultra-rare exomes 364/1,444,744 · genomes 25/152,338 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0534%	1,873
Middle Eastern	0.0496%	2,017
European (non-Finnish)	0.0268%	3,733
Remaining individualsnot grpmax-eligible	0.0258%	3,870
Admixed American	0.0122%	8,178
African / African-American	0.00268%	37,358

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.Arg699Cys
Coding: c.2095C>T
MANE Select: NM_000632
dbSNP: rs538515225
Type: single nucleotide variant
Location: chr16:31324491 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.30 · 31 PDB
Residue 699: a β-strand

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

Similar variants

ITGAM p.Arg699His 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-arg699cys (accessed [today's date]).

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