Is CD74 p.Pro103Ser (c.307C>T) pathogenic?

CD74 p.Pro103Ser (c.307C>T) is classified Uncertain significance in CD74 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely benign (0.13); Very rare (popmax 8.59e-05%, nfe).

How common is CD74 p.Pro103Ser (c.307C>T) in the general population?

CD74 p.Pro103Ser (c.307C>T) is very rare (popmax 8.59e-05%, nfe) (gnomAD).

What do computational predictors say about CD74 p.Pro103Ser (c.307C>T)?

AlphaMissense predicts likely benign (score 0.13) — an in-silico prediction, not a clinical call.

CD74 p.Pro103Ser

c.307C>T · VCV4223030

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.13 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.59e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.13	likely benign
REVEL	0.344	indeterminate
SaProt	LLR -7.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 11 kb · p 0.009 · regional, not allelic
Overall
CADD	23.9	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 8.59e-05% European (non-Finnish) · 1/1,164,522 alleles

Overall 7.06e-05% 1/1,417,006 alleles · very rare

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.Pro103Ser
Coding: c.307C>T
MANE Select: NM_001025159
Type: single nucleotide variant
Location: chr5:150406952 (GRCh38)
Gene constraint: LOEUF 0.849 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.49 · 24 PDB
Residue 103: an α-helix

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-pro103ser (accessed [today's date]).

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