Is CD274 p.Pro146Arg (c.437C>G) pathogenic?

CD274 p.Pro146Arg (c.437C>G) is classified Likely benign in CD274 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). AlphaMissense: likely benign (0.1271); Rare (popmax 0.503%, amr).

How common is CD274 p.Pro146Arg (c.437C>G) in the general population?

CD274 p.Pro146Arg (c.437C>G) is rare (popmax 0.503%, amr) (gnomAD).

What do computational predictors say about CD274 p.Pro146Arg (c.437C>G)?

AlphaMissense predicts likely benign (score 0.1271) — an in-silico prediction, not a clinical call.

CD274 p.Pro146Arg

c.437C>G · rs17718883 · VCV2659049

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1271 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.503%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1271	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -7.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.083, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 12 kb · p 0.73 · regional, not allelic
Overall
CADD	19.99	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 0.503% Admixed American · 302/59,990 alleles

Filtering AF 0.457% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.438%

Overall 0.406% 6,557/1,613,860 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.41%	41
Ashkenazi Jewishnot grpmax-eligible	1.64%	61
Admixed Americangrpmax	0.503%	199
Remaining individualsnot grpmax-eligible	0.45%	222
European (non-Finnish)	0.446%	224
Finnishnot grpmax-eligible	0.206%	485
Middle Eastern	0.0826%	1,211
African / African-American	0.06%	1,667
South Asian	0.0209%	4,793

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: CD274
Protein: p.Pro146Arg
Coding: c.437C>G
MANE Select: NM_014143
dbSNP: rs17718883
Type: single nucleotide variant
Location: chr9:5462876 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 88.13 · 78 PDB
Residue 146: a turn; the ig-like c2-type domain

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

Similar variants

CD274 p.Pro146Thr Uncertain significance ★ ⚠ same residue
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.Glu205Asp Uncertain significance ★ ⚠ same type
CD274 p.Glu217Lys 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-pro146arg (accessed [today's date]).

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