Is CD274 p.Glu205Asp (c.615G>C) pathogenic?

CD274 p.Glu205Asp (c.615G>C) is classified Uncertain significance in CD274 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1323); Very rare (popmax 0.00167%, amr).

How common is CD274 p.Glu205Asp (c.615G>C) in the general population?

CD274 p.Glu205Asp (c.615G>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CD274 p.Glu205Asp (c.615G>C)?

AlphaMissense predicts likely benign (score 0.1323) — an in-silico prediction, not a clinical call.

CD274 p.Glu205Asp

c.615G>C · VCV4222761

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1323 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1323	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.6	GERP -2.6, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 12 kb · p 0.73 · regional, not allelic
Overall
CADD	16.69	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 0.00167% Admixed American · 1/60,006 alleles

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

Overall 0.000547% 8/1,461,620 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,006
European (non-Finnish)	0.000593%	168,547

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: CD274
Protein: p.Glu205Asp
Coding: c.615G>C
MANE Select: NM_014143
Type: single nucleotide variant
Location: chr9:5463054 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 88.13 · 78 PDB
Residue 205: a disulfide bond; the ig-like c2-type domain

Full CD274 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD274 c.*2635A>G Benign ★★ same type
CD274 c.*93G>A Benign ★★ same type
CD274 p.Arg186Ser Uncertain significance ★ ⚠ same type
CD274 p.Asn183Thr Uncertain significance ★ ⚠ same type
CD274 p.Asn278His Uncertain significance ★ ⚠ same type
CD274 p.Glu217Lys Uncertain significance ★ ⚠ same type
CD274 p.Met115Val Uncertain significance ★ ⚠ same type
CD274 p.Pro146Thr 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/cd274-p-glu205asp (accessed [today's date]).

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