Is CD37 p.Ile225Val (c.673A>G) pathogenic?

CD37 p.Ile225Val (c.673A>G) is classified Uncertain significance in CD37 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.0923); Ultra-rare (popmax 0.0784%, amr).

How common is CD37 p.Ile225Val (c.673A>G) in the general population?

CD37 p.Ile225Val (c.673A>G) is ultra-rare (popmax 0.0784%, amr) (gnomAD).

What do computational predictors say about CD37 p.Ile225Val (c.673A>G)?

AlphaMissense predicts likely benign (score 0.0923) — an in-silico prediction, not a clinical call.

CD37 p.Ile225Val

c.673A>G · VCV4222888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0923 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0784%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0923	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -8.22	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 4.4	GERP 4.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 4,784 bp · p 0.63 · regional, not allelic
Overall
CADD	11.41	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 0.0784% Admixed American · 47/59,980 alleles

Filtering AF 0.0605% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.00341% 55/1,612,254 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0784%	1,276
Middle Eastern	0.0164%	6,080
Remaining individualsnot grpmax-eligible	0.00321%	31,201
African / African-American	0.00134%	74,898
European (non-Finnish)	0.000339%	294,658

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: CD37
Protein: p.Ile225Val
Coding: c.673A>G
MANE Select: NM_001774
Type: single nucleotide variant
Location: chr19:49338925 (GRCh38)
Gene constraint: LOEUF 1.215 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.31

Full CD37 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD37 p.Val44= Benign ★★ same type
CD37 p.Ala221Thr Uncertain significance ★ ⚠ same type
CD37 p.Arg112Gly Uncertain significance ★ ⚠ same type
CD37 p.Arg112Pro Uncertain significance ★ ⚠ same type
CD37 p.Arg120Leu Uncertain significance ★ ⚠ same type
CD37 p.Arg281Cys Uncertain significance ★ ⚠ same type
CD37 p.Arg281Ser Uncertain significance ★ ⚠ same type
CD37 p.Asn170Asp 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/cd37-p-ile225val (accessed [today's date]).

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