Is CD74 p.Pro225Leu (c.674C>T) pathogenic?

CD74 p.Pro225Leu (c.674C>T) is classified Uncertain significance in CD74 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-27). AlphaMissense: likely benign (0.2565); Ultra-rare (popmax 0.0165%, mid).

How common is CD74 p.Pro225Leu (c.674C>T) in the general population?

CD74 p.Pro225Leu (c.674C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CD74 p.Pro225Leu (c.674C>T)?

AlphaMissense predicts likely benign (score 0.2565) — an in-silico prediction, not a clinical call.

CD74 p.Pro225Leu

c.674C>T · VCV3488173

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2565 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2565	likely benign
REVEL	0.315	indeterminate
SaProt	LLR -1.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.77 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 11 kb · p 0.009 · regional, not allelic
Overall
CADD	24.8	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00204% 33/1,614,010 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
South Asian	0.00878%	11,386
Admixed American	0.00833%	12,006
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.00127%	78,660

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: CD74
Protein: p.Pro225Leu
Coding: c.674C>T
MANE Select: NM_001025159
Type: single nucleotide variant
Location: chr5:150403264 (GRCh38)
Gene constraint: LOEUF 0.849 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.49 · 24 PDB
Residue 225: a disulfide bond; the thyroglobulin type-1 domain; the 'required for interaction with ctsl' region

Full CD74 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD74 p.Ala117Thr Uncertain significance ★ ⚠ same type
CD74 p.Arg108Gly Uncertain significance ★ ⚠ same type
CD74 p.Arg108His Uncertain significance ★ ⚠ same type
CD74 p.Arg167Ser Uncertain significance ★ ⚠ same type
CD74 p.Arg35Gly Uncertain significance ★ ⚠ same type
CD74 p.Arg46His Uncertain significance ★ ⚠ same type
CD74 p.Arg77Trp Uncertain significance ★ ⚠ same type
CD74 p.Arg94His 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/cd74-p-pro225leu (accessed [today's date]).

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