Is CD74 p.Lys99Asn (c.297G>T) pathogenic?

CD74 p.Lys99Asn (c.297G>T) is classified Uncertain significance in CD74 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). AlphaMissense: ambiguous (0.4284); Very rare (popmax 8.48e-05%, nfe).

How common is CD74 p.Lys99Asn (c.297G>T) in the general population?

CD74 p.Lys99Asn (c.297G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CD74 p.Lys99Asn (c.297G>T)?

AlphaMissense predicts ambiguous (score 0.4284) — an in-silico prediction, not a clinical call.

CD74 p.Lys99Asn

c.297G>T · VCV3998333

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4284 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4284	ambiguous
REVEL	0.141	moderately benign-leaning
SaProt	LLR -8.01	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.001	GERP 0.72, phastCons 0.001
Regional constraint	o/e 0.87	unconstrained · MANE · 11 kb · p 0.009 · regional, not allelic
Overall
CADD	17.96	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 8.48e-05% European (non-Finnish) · 1/1,179,616 alleles

Overall 6.84e-05% 1/1,461,274 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.Lys99Asn
Coding: c.297G>T
MANE Select: NM_001025159
Type: single nucleotide variant
Location: chr5:150407153 (GRCh38)
Gene constraint: LOEUF 0.849 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.49 · 24 PDB

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-lys99asn (accessed [today's date]).

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