Is ERAL1 p.Pro331Ser (c.991C>T) pathogenic?

ERAL1 p.Pro331Ser (c.991C>T) is classified Uncertain significance in ERAL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-20). AlphaMissense: likely benign (0.104); Ultra-rare (popmax 0.0329%, sas).

How common is ERAL1 p.Pro331Ser (c.991C>T) in the general population?

ERAL1 p.Pro331Ser (c.991C>T) is ultra-rare (popmax 0.0329%, sas) (gnomAD).

What do computational predictors say about ERAL1 p.Pro331Ser (c.991C>T)?

AlphaMissense predicts likely benign (score 0.104) — an in-silico prediction, not a clinical call.

ERAL1 p.Pro331Ser

c.991C>T · VCV3276158

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.104 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.104	likely benign
REVEL	0.417	indeterminate
SaProt	LLR -8.36	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 5,515 bp · p 0.27 · regional, not allelic
Overall
CADD	20.2	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% South Asian · 30/91,082 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.00204% 33/1,614,044 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0329%	3,036
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000169%	590,012

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: ERAL1
Protein: p.Pro331Ser
Coding: c.991C>T
MANE Select: NM_005702
Type: single nucleotide variant
Location: chr17:28858994 (GRCh38)
Gene constraint: LOEUF 0.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.44 · 3 PDB

Full ERAL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERAL1 c.411+53G>A Benign ★★ same type
ERAL1 c.*218C>T Benign ★★ same type
ERAL1 c.*65G>T Benign ★★ same type
ERAL1 p.Ala337= Likely benign ★★ same type
ERAL1 p.Asp315= Benign ★★ same type
ERAL1 p.Ala121Val Uncertain significance ★ ⚠ same type
ERAL1 p.Ala3Val Uncertain significance ★ ⚠ same type
ERAL1 p.Ala51Thr 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/eral1-p-pro331ser (accessed [today's date]).

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