Is CD74 p.Thr258Met (c.773C>T) pathogenic?

CD74 p.Thr258Met (c.773C>T) is classified Uncertain significance in CD74 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-04). AlphaMissense: likely benign (0.3195); Very rare (popmax 0.00223%, eas).

How common is CD74 p.Thr258Met (c.773C>T) in the general population?

CD74 p.Thr258Met (c.773C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CD74 p.Thr258Met (c.773C>T)?

AlphaMissense predicts likely benign (score 0.3195) — an in-silico prediction, not a clinical call.

CD74 p.Thr258Met

c.773C>T · VCV4223024

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3195 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3195	likely benign
REVEL	0.296	indeterminate
SaProt	LLR -8.79	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 12	GERP -0.31, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 11 kb · p 0.009 · regional, not allelic
Overall
CADD	29.7	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 0.00223% East Asian · 1/44,894 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000806% 13/1,613,864 alleles · very rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.439%	228
East Asiangrpmax	0.00223%	44,894
Remaining individualsnot grpmax-eligible	0.0016%	62,466
European (non-Finnish)	0.000593%	168,555

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr258Met
Coding: c.773C>T
MANE Select: NM_001025159
Type: single nucleotide variant
Location: chr5:150403165 (GRCh38)
Gene constraint: LOEUF 0.849 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.49 · 24 PDB
Residue 258: a disulfide bond; the thyroglobulin type-1 domain

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-thr258met (accessed [today's date]).

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