Is EFS p.Pro180Ser (c.538C>T) pathogenic?

EFS p.Pro180Ser (c.538C>T) is classified Uncertain significance in EFS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-17). AlphaMissense: likely benign (0.0627); Ultra-rare (popmax 0.015%, afr).

How common is EFS p.Pro180Ser (c.538C>T) in the general population?

EFS p.Pro180Ser (c.538C>T) is ultra-rare (popmax 0.015%, afr) (gnomAD).

What do computational predictors say about EFS p.Pro180Ser (c.538C>T)?

AlphaMissense predicts likely benign (score 0.0627) — an in-silico prediction, not a clinical call.

EFS p.Pro180Ser

c.538C>T · rs575887252 · VCV2326287

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0627 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0627	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -6.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1	GERP -3.5
Regional constraint	o/e 0.98	unconstrained · MANE · 7,796 bp · p 0.65 · regional, not allelic
Overall
CADD	0.199	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 0.015% African / African-American · 11/73,482 alleles

Filtering AF 0.00831% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00644%

Overall 0.000832% 13/1,563,256 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.015%	6,680
Remaining individualsnot grpmax-eligible	0.00166%	60,334
European (non-Finnish)	8.65e-05%	1,156,016

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: EFS
Protein: p.Pro180Ser
Coding: c.538C>T
MANE Select: NM_005864
dbSNP: rs575887252
Type: single nucleotide variant
Location: chr14:23359940 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.71
Residue 180: the 'disordered' region

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

Similar variants

EFS p.Pro141= Benign ★★ same type
EFS p.Ala167Thr Uncertain significance ★ ⚠ same type
EFS p.Ala186Val Uncertain significance ★ ⚠ same type
EFS p.Ala219Asp Uncertain significance ★ ⚠ same type
EFS p.Ala262Ser Uncertain significance ★ ⚠ same type
EFS p.Ala285Ser Uncertain significance ★ ⚠ same type
EFS p.Ala40Val Uncertain significance ★ ⚠ same type
EFS p.Ala495Pro 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/efs-p-pro180ser (accessed [today's date]).

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