Is ERC2 p.Leu708Phe (c.2122C>T) pathogenic?

ERC2 p.Leu708Phe (c.2122C>T) is classified Uncertain significance in ERC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely benign (0.204); Ultra-rare (popmax 0.0485%, nfe).

How common is ERC2 p.Leu708Phe (c.2122C>T) in the general population?

ERC2 p.Leu708Phe (c.2122C>T) is ultra-rare (popmax 0.0485%, nfe) (gnomAD).

What do computational predictors say about ERC2 p.Leu708Phe (c.2122C>T)?

AlphaMissense predicts likely benign (score 0.204) — an in-silico prediction, not a clinical call.

ERC2 p.Leu708Phe

c.2122C>T · rs139250346 · VCV2347832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.204 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0485%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.204	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -9.09	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 9.8	GERP 4.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 323 kb · p 0.17 · regional, not allelic
Overall
CADD	27.5	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 0.0485% European (non-Finnish) · 572/1,179,804 alleles

Filtering AF 0.0452% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0438%

Overall 0.0372% 601/1,613,788 alleles · ultra-rare exomes 562/1,461,598 · genomes 39/152,190 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0485%	2,063
Remaining individualsnot grpmax-eligible	0.0256%	3,905
Middle Eastern	0.0165%	6,062
Admixed American	0.0133%	7,499
African / African-American	0.00533%	18,746

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: ERC2
Protein: p.Leu708Phe
Coding: c.2122C>T
MANE Select: NM_015576
dbSNP: rs139250346
Type: single nucleotide variant
Location: chr3:55992190 (GRCh38)
Gene constraint: LOEUF 0.476 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 74.26

Full ERC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERC2 p.Ala105Ser Uncertain significance ★ ⚠ same type
ERC2 p.Ala107Thr Uncertain significance ★ ⚠ same type
ERC2 p.Ala202Val Uncertain significance ★ ⚠ same type
ERC2 p.Ala251Val Uncertain significance ★ ⚠ same type
ERC2 p.Ala333Ser Uncertain significance ★ ⚠ same type
ERC2 p.Ala371Pro Uncertain significance ★ ⚠ same type
ERC2 p.Ala724Thr Uncertain significance ★ ⚠ same type
ERC2 p.Ala835Thr 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/erc2-p-leu708phe (accessed [today's date]).

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