Is EPYC p.Pro50His (c.149C>A) pathogenic?

EPYC p.Pro50His (c.149C>A) is classified Uncertain significance in EPYC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely benign (0.1062); Ultra-rare (popmax 0.0485%, amr).

How common is EPYC p.Pro50His (c.149C>A) in the general population?

EPYC p.Pro50His (c.149C>A) is ultra-rare (popmax 0.0485%, amr) (gnomAD).

What do computational predictors say about EPYC p.Pro50His (c.149C>A)?

AlphaMissense predicts likely benign (score 0.1062) — an in-silico prediction, not a clinical call.

EPYC p.Pro50His

c.149C>A · rs772023724 · VCV2363128

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1062 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0485%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1062	likely benign
REVEL	0.104	moderately benign-leaning
SaProt	LLR -8.19	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 7.3	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.94 · regional, not allelic
Overall
CADD	22.2	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 0.0485% Admixed American · 29/59,740 alleles

Filtering AF 0.0346% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.03%

Overall 0.00248% 40/1,612,036 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0485%	2,060
Remaining individualsnot grpmax-eligible	0.016%	6,240
European (non-Finnish)	8.48e-05%	1,179,188

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: EPYC
Protein: p.Pro50His
Coding: c.149C>A
MANE Select: NM_004950
dbSNP: rs772023724
Type: single nucleotide variant
Location: chr12:91002417 (GRCh38)
Gene constraint: LOEUF 1.396 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.83

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

Similar variants

EPYC p.Ala137Val Uncertain significance ★ ⚠ same type
EPYC p.Ala16Asp Uncertain significance ★ ⚠ same type
EPYC p.Ala16Thr Uncertain significance ★ ⚠ same type
EPYC p.Ala35Pro Uncertain significance ★ ⚠ same type
EPYC p.Arg194Gln Uncertain significance ★ ⚠ same type
EPYC p.Arg199Cys Uncertain significance ★ ⚠ same type
EPYC p.Arg199His Uncertain significance ★ ⚠ same type
EPYC p.Arg261Gln 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/epyc-p-pro50his (accessed [today's date]).

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