Is ERF p.Pro221Leu (c.662C>T) pathogenic?

ERF p.Pro221Leu (c.662C>T) is classified Uncertain significance in ERF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely benign (0.1263); Very rare (popmax 0.00449%, sas).

How common is ERF p.Pro221Leu (c.662C>T) in the general population?

ERF p.Pro221Leu (c.662C>T) is very rare (popmax 0.00449%, sas) (gnomAD).

What do computational predictors say about ERF p.Pro221Leu (c.662C>T)?

AlphaMissense predicts likely benign (score 0.1263) — an in-silico prediction, not a clinical call.

ERF p.Pro221Leu

c.662C>T · VCV4534283

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1263 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00449%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1263	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -7.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.67, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 1,421 bp · p 0.024 · regional, not allelic
Overall
CADD	21.7	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 0.00449% South Asian · 4/89,106 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000906%

Overall 0.000752% 12/1,596,350 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00449%	22,276
Ashkenazi Jewishnot grpmax-eligible	0.00351%	28,488
Admixed American	0.00173%	57,922
European (non-Finnish)	0.000512%	195,380

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: ERF
Protein: p.Pro221Leu
Coding: c.662C>T
MANE Select: NM_006494
Type: single nucleotide variant
Location: chr19:42249450 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.46 · 2 PDB
Residue 221: the 'disordered' region

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

Similar variants

ERF p.Pro221Ala Uncertain significance ★ ⚠ same residue
ERF p.Arg183Ter Pathogenic ★★ same type
ERF p.Arg207Ter Pathogenic/Likely pathogenic ★★ same type
ERF p.Arg218Ter Pathogenic/Likely pathogenic ★★ same type
ERF p.Arg233Ter Pathogenic ★★ same type
ERF p.Arg86Cys Pathogenic/Likely pathogenic ★★ same type
ERF p.Gln263Ter Pathogenic ★★ same type
ERF p.Gly53Arg 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/erf-p-pro221leu (accessed [today's date]).

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