Is EPYC p.Arg199His (c.596G>A) pathogenic?

EPYC p.Arg199His (c.596G>A) is classified Uncertain significance in EPYC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-02). AlphaMissense: ambiguous (0.434); Ultra-rare (popmax 0.012%, afr).

How common is EPYC p.Arg199His (c.596G>A) in the general population?

EPYC p.Arg199His (c.596G>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about EPYC p.Arg199His (c.596G>A)?

AlphaMissense predicts ambiguous (score 0.434) — an in-silico prediction, not a clinical call.

EPYC p.Arg199His

c.596G>A · rs745867926 · VCV3090017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.434 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.434	ambiguous
REVEL	0.253	benign-leaning
SaProt	LLR -6.29	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.94 · regional, not allelic
Overall
CADD	32.0	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 0.012% African / African-American · 9/74,814 alleles

Filtering AF 0.00648% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00601%

Overall 0.00775% 125/1,611,868 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0176%	5,669
African / African-Americangrpmax	0.012%	8,313
East Asian	0.00894%	11,181
European (non-Finnish)	0.0078%	12,816
South Asian	0.0066%	15,145
Admixed American	0.00503%	19,865

Remaining individuals 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: EPYC
Protein: p.Arg199His
Coding: c.596G>A
MANE Select: NM_004950
dbSNP: rs745867926
Type: single nucleotide variant
Location: chr12:90971906 (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.Arg199Cys Uncertain significance ★ ⚠ same residue
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.Arg261Gln Uncertain significance ★ ⚠ same type
EPYC p.Arg288His 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-arg199his (accessed [today's date]).

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