Is ERC1 p.Ser995Tyr (c.2984C>A) pathogenic?

ERC1 p.Ser995Tyr (c.2984C>A) is classified Uncertain significance in ERC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-25). AlphaMissense: likely benign (0.1425); Ultra-rare (popmax 0.01%, amr).

How common is ERC1 p.Ser995Tyr (c.2984C>A) in the general population?

ERC1 p.Ser995Tyr (c.2984C>A) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about ERC1 p.Ser995Tyr (c.2984C>A)?

AlphaMissense predicts likely benign (score 0.1425) — an in-silico prediction, not a clinical call.

ERC1 p.Ser995Tyr

c.2984C>A · VCV3509777

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1425 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1425	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -8.39	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 4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 462 kb · p 5.7e-05 · regional, not allelic
Overall
CADD	24.3	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 0.01% Admixed American · 6/59,992 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000744% 12/1,613,878 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,999
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-American	0.00133%	74,910
European (non-Finnish)	0.000339%	294,991

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: ERC1
Protein: p.Ser995Tyr
Coding: c.2984C>A
MANE Select: NM_178040
Type: single nucleotide variant
Location: chr12:1408207 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 75.64

Full ERC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ERC1 p.Ser393= Benign ★★ same type
ERC1 c.3214-1G>A Uncertain significance ★ same type
ERC1 p.Ala1058Val Uncertain significance ★ ⚠ same type
ERC1 p.Ala199Thr Uncertain significance ★ ⚠ same type
ERC1 p.Ala260Glu Uncertain significance ★ ⚠ same type
ERC1 p.Ala5Ser Uncertain significance ★ ⚠ same type
ERC1 p.Ala621Thr Uncertain significance ★ ⚠ same type
ERC1 p.Ala682Ser 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/erc1-p-ser995tyr (accessed [today's date]).

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