Is EARS2 p.Ser439Leu (c.1316C>T) pathogenic?

EARS2 p.Ser439Leu (c.1316C>T) is classified Uncertain significance in EARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-08). AlphaMissense: likely benign (0.1941); Very rare (popmax 0.005%, amr).

How common is EARS2 p.Ser439Leu (c.1316C>T) in the general population?

EARS2 p.Ser439Leu (c.1316C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about EARS2 p.Ser439Leu (c.1316C>T)?

AlphaMissense predicts likely benign (score 0.1941) — an in-silico prediction, not a clinical call.

EARS2 p.Ser439Leu

c.1316C>T · rs747235837 · VCV2420469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1941 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1941	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -10.22	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 11 kb · p 0.22 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,986 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00161% 26/1,614,022 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,995
African / African-American	0.00267%	37,461
European (non-Finnish)	0.00169%	59,001
South Asian	0.0011%	91,068

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: EARS2
Protein: p.Ser439Leu
Coding: c.1316C>T
MANE Select: NM_001083614
dbSNP: rs747235837
Type: single nucleotide variant
Location: chr16:23529538 (GRCh38)
Gene constraint: LOEUF 1.138 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.84

Full EARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EARS2 p.Ser439= Benign/Likely benign ★★ same residue
EARS2 p.Arg107His Pathogenic/Likely pathogenic ★★ ⚠ same type
EARS2 p.Arg108Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
EARS2 p.Cys167Tyr Pathogenic/Likely pathogenic ★★ same type
EARS2 p.Gly317Cys Pathogenic ★★ same type
EARS2 p.Met1Val Pathogenic/Likely pathogenic ★★ same type
EARS2 p.Ser143Ter Pathogenic ★★ same type
EARS2 p.Ala263Thr 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/ears2-p-ser439leu (accessed [today's date]).

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