Is EPYC p.Ser180Pro (c.538T>C) pathogenic?

EPYC p.Ser180Pro (c.538T>C) is classified Uncertain significance in EPYC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-10). AlphaMissense: likely pathogenic (0.8487); Ultra-rare (popmax 0.0578%, amr).

How common is EPYC p.Ser180Pro (c.538T>C) in the general population?

EPYC p.Ser180Pro (c.538T>C) is ultra-rare (popmax 0.0578%, amr) (gnomAD).

What do computational predictors say about EPYC p.Ser180Pro (c.538T>C)?

AlphaMissense predicts likely pathogenic (score 0.8487) — an in-silico prediction, not a clinical call.

EPYC p.Ser180Pro

c.538T>C · VCV3509711

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8487 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0578%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8487	likely pathogenic
REVEL	0.392	indeterminate
SaProt	LLR -13.72	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 38 kb · p 0.94 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0578% Admixed American · 34/58,834 alleles

Filtering AF 0.0424% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0372%

Overall 0.00299% 48/1,606,028 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0578%	1,730
African / African-American	0.00267%	37,394
European (non-Finnish)	0.00102%	97,988

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.Ser180Pro
Coding: c.538T>C
MANE Select: NM_004950
Type: single nucleotide variant
Location: chr12:90971964 (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-ser180pro (accessed [today's date]).

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