Is ITGAM p.Pro1146Ser (c.3436C>T) pathogenic?

ITGAM p.Pro1146Ser (c.3436C>T) is classified Benign in ITGAM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0763); Common (popmax 25.2%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ITGAM p.Pro1146Ser (c.3436C>T)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

ITGAM p.Pro1146Ser

Q: How common is ITGAM p.Pro1146Ser (c.3436C>T) in the general population?

ITGAM p.Pro1146Ser (c.3436C>T) is common (popmax 25.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3436C>T · rs1143678 · VCV1164969

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 25.2%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -5.95	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 1.2	GERP -1.4, phastCons 0.009
Regional constraint	o/e 0.91	unconstrained · MANE · 72 kb · p 0.00026 · regional, not allelic
Overall
CADD	18.63	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 25.2% Middle Eastern · 1,520/6,042 alleles

Filtering AF 24.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.6%

Overall 15.4% 247,761/1,606,686 alleles · common exomes 221,942/1,454,664 · genomes 25,819/152,022 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	25.2%	4
South Asian	25%	4
Ashkenazi Jewishnot grpmax-eligible	21.5%	5
African / African-American	21.2%	5
Amishnot grpmax-eligible	19.3%	5
Remaining individualsnot grpmax-eligible	16.6%	6
European (non-Finnish)	14.9%	7
Finnishnot grpmax-eligible	12.6%	8
Admixed American	11.9%	8
East Asian	0.591%	169

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.Pro1146Ser
Coding: c.3436C>T
MANE Select: NM_000632
dbSNP: rs1143678
Type: single nucleotide variant
Location: chr16:31331684 (GRCh38)
Gene constraint: LOEUF 0.678 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.30 · 31 PDB
Residue 1146: a UniProt-annotated variant site (in)

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

Similar variants

ITGAM p.Pro1146fs 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-pro1146ser (accessed [today's date]).

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