Is ITGAM p.Arg77Cys (c.229C>T) pathogenic?

ITGAM p.Arg77Cys (c.229C>T) is classified Uncertain significance in ITGAM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-02). AlphaMissense: likely benign (0.1299); Very rare (popmax 0.00418%, nfe).

How common is ITGAM p.Arg77Cys (c.229C>T) in the general population?

ITGAM p.Arg77Cys (c.229C>T) is very rare (popmax 0.00418%, nfe) (gnomAD).

What do computational predictors say about ITGAM p.Arg77Cys (c.229C>T)?

AlphaMissense predicts likely benign (score 0.1299) — an in-silico prediction, not a clinical call.

ITGAM p.Arg77Cys

c.229C>T · rs778435275 · VCV1409930

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1299 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00418%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1299	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -11.68	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.2	GERP -4.2
Regional constraint	o/e 0.91	unconstrained · MANE · 72 kb · p 0.00026 · regional, not allelic
Overall
CADD	17.17	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 0.00418% European (non-Finnish) · 49/1,171,800 alleles

Filtering AF 0.0032% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00288%

Overall 0.00326% 52/1,596,962 alleles · very rare exomes 50/1,444,788 · genomes 2/152,174 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00418%	23,914
Admixed American	0.0035%	28,594
Remaining individualsnot grpmax-eligible	0.00162%	61,768

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.Arg77Cys
Coding: c.229C>T
MANE Select: NM_000632
dbSNP: rs778435275
Type: single nucleotide variant
Location: chr16:31265489 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.30 · 31 PDB
Residue 77: a UniProt-annotated variant site (influences susceptibility to sle)

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

Similar variants

ITGAM p.Arg77His Benign ★★ same residue
ITGAM p.Arg77= 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-arg77cys (accessed [today's date]).

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