Is ECE2 p.Pro508Arg (c.1523C>G) pathogenic?

ECE2 p.Pro508Arg (c.1523C>G) is classified Uncertain significance in ECE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-20). AlphaMissense: likely benign (0.1547); Rare (popmax 0.132%, mid).

How common is ECE2 p.Pro508Arg (c.1523C>G) in the general population?

ECE2 p.Pro508Arg (c.1523C>G) is rare (popmax 0.132%, mid) (gnomAD).

What do computational predictors say about ECE2 p.Pro508Arg (c.1523C>G)?

AlphaMissense predicts likely benign (score 0.1547) — an in-silico prediction, not a clinical call.

ECE2 p.Pro508Arg

c.1523C>G · rs144817798 · VCV3086906

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1547 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1547	likely benign
REVEL	0.541	indeterminate
SaProt	LLR -8.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.83, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.014 · regional, not allelic
Overall
CADD	24.2	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P554R vs ClinVar P508R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.132% Middle Eastern · 8/6,070 alleles

Filtering AF 0.0656% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.00955% 154/1,613,256 alleles · rare exomes 144/1,461,180 · genomes 10/152,076 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	759
Remaining individualsnot grpmax-eligible	0.0304%	3,287
Admixed American	0.0134%	7,491
European (non-Finnish)	0.00941%	10,628
South Asian	0.0055%	18,196
African / African-American	0.00401%	24,955

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: ECE2
Protein: p.Pro508Arg
Coding: c.1523C>G
MANE Select: NM_001100121
dbSNP: rs144817798
Type: single nucleotide variant
Location: chr3:184289690 (GRCh38)
Gene constraint: LOEUF 0.965 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 554 UniProt numbering: the peptidase m13 domain

Full ECE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ECE2 p.Arg453Gln Benign ★★ same type
ECE2 p.Ser400= Benign ★★ same type
ECE2 p.Val248= Benign ★★ same type
EEF1AKMT4-ECE2 p.Val127Ala Benign ★★ same type
ECE2 p.Ala338Val Uncertain significance ★ ⚠ same type
ECE2 p.Ala437Thr Uncertain significance ★ ⚠ same type
ECE2 p.Ala575Thr Uncertain significance ★ ⚠ same type
ECE2 p.Ala638Gly 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/ece2-p-pro508arg (accessed [today's date]).

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