Is ITGAM p.Arg246Gln (c.737G>A) pathogenic?

ITGAM p.Arg246Gln (c.737G>A) is classified Benign in ITGAM (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-27). AlphaMissense: likely benign (0.177); Rare (popmax 0.132%, nfe).

How common is ITGAM p.Arg246Gln (c.737G>A) in the general population?

ITGAM p.Arg246Gln (c.737G>A) is rare (popmax 0.132%, nfe) (gnomAD).

What do computational predictors say about ITGAM p.Arg246Gln (c.737G>A)?

AlphaMissense predicts likely benign (score 0.177) — an in-silico prediction, not a clinical call.

ITGAM p.Arg246Gln

c.737G>A · rs199671976 · VCV1164680

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.177 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.177	likely benign
REVEL	0.282	benign-leaning
SaProt	LLR -11.47	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 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 72 kb · p 0.00026 · regional, not allelic
Overall
CADD	29.3	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 0.132% European (non-Finnish) · 1,556/1,179,786 alleles

Filtering AF 0.126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.124%

Overall 0.164% 2,642/1,613,690 alleles · rare exomes 2,421/1,461,614 · genomes 221/152,076 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.72%	37
Amishnot grpmax-eligible	0.877%	114
Remaining individualsnot grpmax-eligible	0.256%	391
European (non-Finnish)grpmax	0.132%	758
Admixed American	0.0517%	1,935
Middle Eastern	0.0495%	2,021
Finnishnot grpmax-eligible	0.0422%	2,369
South Asian	0.0351%	2,846
African / African-American	0.0267%	3,748

Ashkenazi Jewish 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.Arg246Gln
Coding: c.737G>A
MANE Select: NM_000632
dbSNP: rs199671976
Type: single nucleotide variant
Location: chr16:31273397 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.30 · 31 PDB
Residue 246: the vwfa domain

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

Similar variants

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
ITGAM p.Arg224Trp 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-arg246gln (accessed [today's date]).

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