Is ITGAM p.Arg77His (c.230G>A) pathogenic?

ITGAM p.Arg77His (c.230G>A) is classified Benign in ITGAM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0589); Common (popmax 15.5%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ITGAM p.Arg77His (c.230G>A)?

AlphaMissense predicts likely benign (score 0.0589) — an in-silico prediction, not a clinical call.

ITGAM p.Arg77His

Q: How common is ITGAM p.Arg77His (c.230G>A) in the general population?

ITGAM p.Arg77His (c.230G>A) is common (popmax 15.5%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.230G>A · rs1143679 · VCV1164965

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0589 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 15.5%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0589	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -7.65	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 -6.2	GERP -4.2
Regional constraint	o/e 0.91	unconstrained · MANE · 72 kb · p 0.00026 · regional, not allelic
Overall
CADD	0.106	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 15.5% Middle Eastern · 932/6,010 alleles

Filtering AF 14.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.4%

Overall 10.1% 161,393/1,592,706 alleles · common exomes 144,937/1,440,550 · genomes 16,456/152,156 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	19.1%	5
Middle Easterngrpmax	15.5%	6
Ashkenazi Jewishnot grpmax-eligible	14.2%	7
Finnishnot grpmax-eligible	11.6%	9
Remaining individualsnot grpmax-eligible	10.9%	9
African / African-American	10.7%	9
European (non-Finnish)	10.5%	10
Admixed American	8.55%	12
South Asian	7.15%	14
East Asian	0.238%	420

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg77His
Coding: c.230G>A
MANE Select: NM_000632
dbSNP: rs1143679
Type: single nucleotide variant
Location: chr16:31265490 (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.Arg77Cys Uncertain significance ★★ ⚠ 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-arg77his (accessed [today's date]).

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