Is EARS2 p.Phe271= (c.813C>T) pathogenic?

EARS2 p.Phe271= (c.813C>T) is classified Benign/Likely benign in EARS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-26). Rare (popmax 0.439%, afr); Associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome.

How common is EARS2 p.Phe271= (c.813C>T) in the general population?

EARS2 p.Phe271= (c.813C>T) is rare (popmax 0.439%, afr) (gnomAD).

EARS2 p.Phe271=

Q: What condition is associated with EARS2 p.Phe271= (c.813C>T)?

EARS2 p.Phe271= (c.813C>T) is associated with leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (ClinVar).

Q: How is Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome inherited?

Typically No data available (Orphanet). A genetic counselor can assess individual risk for a family.

c.813C>T · rs149664520 · VCV380296

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.439%, afr)

Conditions

leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.3	GERP -3.1, phastCons 0.4
Overall
CADD	7.477	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.439% African / African-American · 329/75,008 alleles

Filtering AF 0.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.384%

Overall 0.034% 548/1,610,942 alleles · rare exomes 330/1,458,610 · genomes 218/152,332 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.439%	228
Admixed American	0.047%	2,129
Middle Eastern	0.037%	2,702
Remaining individualsnot grpmax-eligible	0.0305%	3,281
European (non-Finnish)	0.0138%	7,233
South Asian	0.00442%	22,643
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,546
East Asian	0.00223%	44,806
Finnishnot grpmax-eligible	0.00157%	63,800

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.Phe271=
Coding: c.813C>T
MANE Select: NM_001083614
dbSNP: rs149664520
Type: single nucleotide variant
Location: chr16:23535033 (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

Disease context

leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (Orphanet):

Inheritance: No data available
Onset: Infancy, Neonatal

Similar variants

EARS2 p.Arg107His Pathogenic/Likely pathogenic ★★ ⚠ same condition
EARS2 p.Arg108Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
EARS2 p.Cys167Tyr Pathogenic/Likely pathogenic ★★ same condition
EARS2 p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
EARS2 p.Ser143Ter Pathogenic ★★ same condition
EARS2 p.Arg162Trp Uncertain significance ★★ ⚠ same condition
EARS2 p.Arg188His Uncertain significance ★★ ⚠ same condition
EARS2 p.Arg361Trp Uncertain significance ★★ ⚠ same condition

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-phe271 (accessed [today's date]).

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