Is ELFN1 p.Pro712Leu (c.2135C>T) pathogenic?

ELFN1 p.Pro712Leu (c.2135C>T) is classified Uncertain significance in ELFN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-23). AlphaMissense: likely benign (0.0883); Ultra-rare (popmax 0.0388%, amr).

How common is ELFN1 p.Pro712Leu (c.2135C>T) in the general population?

ELFN1 p.Pro712Leu (c.2135C>T) is ultra-rare (popmax 0.0388%, amr) (gnomAD).

What do computational predictors say about ELFN1 p.Pro712Leu (c.2135C>T)?

AlphaMissense predicts likely benign (score 0.0883) — an in-silico prediction, not a clinical call.

ELFN1 p.Pro712Leu

c.2135C>T · rs995483045 · VCV2355800

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0883 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0388%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.0883	likely benign
SaProt	LLR -6.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.56	GERP -1.4
Regional constraint	o/e 1.05	unconstrained · MANE · 1,744 bp · p 0.16 · regional, not allelic
Overall
CADD	18.63	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 0.0388% Admixed American · 17/43,764 alleles

Filtering AF 0.0247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0203%

Overall 0.00411% 61/1,483,384 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0388%	2,574
East Asian	0.00563%	17,757
European (non-Finnish)	0.00374%	26,750

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: ELFN1
Protein: p.Pro712Leu
Coding: c.2135C>T
MANE Select: NM_001128636
dbSNP: rs995483045
Type: single nucleotide variant
Location: chr7:1746731 (GRCh38)
Gene constraint: LOEUF 1.841 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 5 PDB
Residue 712: the 'disordered' region

Full ELFN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ELFN1 p.Ala14= Benign/Likely benign ★★ same type
ELFN1 p.Ala796= Benign/Likely benign ★★ same type
ELFN1 p.Asp618= Likely benign ★★ same type
ELFN1 p.Cys196= Likely benign ★★ same type
ELFN1 p.Glu258= Benign/Likely benign ★★ same type
ELFN1 p.Gly228= Benign/Likely benign ★★ same type
ELFN1 p.His20= Benign/Likely benign ★★ same type
ELFN1 p.Pro614= Benign/Likely benign ★★ 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/elfn1-p-pro712leu (accessed [today's date]).

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