Is EEFSEC p.Pro180Leu (c.539C>T) pathogenic?

EEFSEC p.Pro180Leu (c.539C>T) is classified Uncertain significance in EEFSEC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-22). AlphaMissense: likely benign (0.1124); Ultra-rare (popmax 0.0547%, afr).

How common is EEFSEC p.Pro180Leu (c.539C>T) in the general population?

EEFSEC p.Pro180Leu (c.539C>T) is ultra-rare (popmax 0.0547%, afr) (gnomAD).

What do computational predictors say about EEFSEC p.Pro180Leu (c.539C>T)?

AlphaMissense predicts likely benign (score 0.1124) — an in-silico prediction, not a clinical call.

EEFSEC p.Pro180Leu

c.539C>T · rs369240402 · VCV3087348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1124 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0547%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1124	likely benign
REVEL	0.672	pathogenic-leaning
SaProt	LLR -11.50	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 255 kb · p 0.039 · regional, not allelic
Overall
CADD	27.9	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 0.0547% African / African-American · 41/74,974 alleles

Filtering AF 0.0413% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0367%

Overall 0.00316% 51/1,614,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0547%	1,829
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000763%	131,112

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: EEFSEC
Protein: p.Pro180Leu
Coding: c.539C>T
MANE Select: NM_021937
dbSNP: rs369240402
Type: single nucleotide variant
Location: chr3:128262142 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 180: the tr-type g domain

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

Similar variants

EEFSEC p.Pro180= Benign ★★ same residue
EEFSEC p.Arg285Gln Uncertain significance ★★ ⚠ same type
EEFSEC p.Arg424Gln Uncertain significance ★★ ⚠ same type
EEFSEC p.Phe463Leu Uncertain significance ★★ ⚠ same type
EEFSEC p.Ala435Val Benign ★★ same type
EEFSEC p.Phe581Cys Benign ★★ same type
EEFSEC p.Asp390Ala Likely pathogenic ★ ⚠ same type
EEFSEC p.Glu514Ter Likely pathogenic ★ 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/eefsec-p-pro180leu (accessed [today's date]).

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