Is ITGAM p.Ala753Val (c.2258C>T) pathogenic?

ITGAM p.Ala753Val (c.2258C>T) is classified Uncertain significance in ITGAM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1877); Ultra-rare (popmax 0.0164%, amr).

How common is ITGAM p.Ala753Val (c.2258C>T) in the general population?

ITGAM p.Ala753Val (c.2258C>T) is ultra-rare (popmax 0.0164%, amr) (gnomAD).

What do computational predictors say about ITGAM p.Ala753Val (c.2258C>T)?

AlphaMissense predicts likely benign (score 0.1877) — an in-silico prediction, not a clinical call.

ITGAM p.Ala753Val

c.2258C>T · rs375408663 · VCV2040757

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1877 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1877	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -9.14	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 2.8	GERP 0.18, phastCons 0.99
Regional constraint	o/e 0.91	unconstrained · MANE · 72 kb · p 0.00026 · regional, not allelic
Overall
CADD	20.7	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 0.0164% Admixed American · 9/54,858 alleles

Filtering AF 0.00849% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00636%

Overall 0.00436% 69/1,581,166 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0164%	6,095
East Asian	0.0134%	7,460
Remaining individualsnot grpmax-eligible	0.00984%	10,167
Ashkenazi Jewishnot grpmax-eligible	0.00741%	13,503
European (non-Finnish)	0.00378%	26,486
African / African-American	0.00271%	36,852

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.Ala753Val
Coding: c.2258C>T
MANE Select: NM_000632
dbSNP: rs375408663
Type: single nucleotide variant
Location: chr16:31324751 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.30 · 31 PDB

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

Similar variants

ITGAM p.Ala753= 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.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-ala753val (accessed [today's date]).

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