Is CD38 p.Thr258Ile (c.773C>T) pathogenic?

CD38 p.Thr258Ile (c.773C>T) is classified Uncertain significance in CD38 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-21). AlphaMissense: ambiguous (0.4448); Very rare (popmax 0.000855%, nfe).

How common is CD38 p.Thr258Ile (c.773C>T) in the general population?

CD38 p.Thr258Ile (c.773C>T) is very rare (popmax 0.000855%, nfe) (gnomAD).

What do computational predictors say about CD38 p.Thr258Ile (c.773C>T)?

AlphaMissense predicts ambiguous (score 0.4448) — an in-silico prediction, not a clinical call.

CD38 p.Thr258Ile

c.773C>T · VCV4650626

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4448 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000855%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4448	ambiguous
REVEL	0.237	benign-leaning
SaProt	LLR -12.56	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.93, phastCons 0.008
Regional constraint	o/e 1.02	unconstrained · MANE · 70 kb · p 0.67 · regional, not allelic
Overall
CADD	14.25	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 0.000855% European (non-Finnish) · 10/1,170,268 alleles

Filtering AF 0.000432% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000315%

Overall 0.000689% 10/1,450,348 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: CD38
Protein: p.Thr258Ile
Coding: c.773C>T
MANE Select: NM_001775
Type: single nucleotide variant
Location: chr4:15840472 (GRCh38)
Gene constraint: LOEUF 1.292 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.09 · 56 PDB
Residue 258: a disulfide bond; an α-helix

Full CD38 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD38 p.Tyr70= Benign ★★ same type
CD38 c.752+2T>C Uncertain significance ★ same type
CD38 p.Ala154Val Uncertain significance ★ ⚠ same type
CD38 p.Arg17Trp Uncertain significance ★ ⚠ same type
CD38 p.Arg194Cys Uncertain significance ★ ⚠ same type
CD38 p.Arg195Gly Uncertain significance ★ ⚠ same type
CD38 p.Asn169Ser Uncertain significance ★ ⚠ same type
CD38 p.Asn209His 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/cd38-p-thr258ile (accessed [today's date]).

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