Is SURF1 p.Phe181= (c.543C>T) pathogenic?

SURF1 p.Phe181= (c.543C>T) is classified Benign/Likely benign in SURF1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 22.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Leigh syndrome.

What condition is associated with SURF1 p.Phe181= (c.543C>T)?

SURF1 p.Phe181= (c.543C>T) is associated with Leigh syndrome (ClinVar).

How is Leigh syndrome inherited?

Typically Autosomal recessive, Mitochondrial inheritance (Orphanet). A genetic counselor can assess individual risk for a family.

SURF1 p.Phe181=

Q: How common is SURF1 p.Phe181= (c.543C>T) in the general population?

SURF1 p.Phe181= (c.543C>T) is common (popmax 22.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.543C>T · rs62637580 · VCV215225

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 22.7%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Leigh syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.32	acceptor loss · deltas
Pangolin	Δ0.29	loss · gain 0.07 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.019	GERP -0.95, phastCons 0.019
Overall
CADD	5.024	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 22.7% East Asian · 10,194/44,858 alleles

Filtering AF 22.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 22.2%

Overall 0.91% 14,680/1,612,502 alleles · common exomes 12,676/1,460,182 · genomes 2,004/152,320 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	22.7%	4
Remaining individualsnot grpmax-eligible	1.38%	72
African / African-American	1.3%	77
South Asian	1.16%	87
Ashkenazi Jewishnot grpmax-eligible	0.981%	102
Middle Eastern	0.598%	167
Admixed American	0.269%	372
European (non-Finnish)	0.093%	1,075
Finnishnot grpmax-eligible	0.0344%	2,907

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: SURF1
Protein: p.Phe181=
Coding: c.543C>T
MANE Select: NM_003172
dbSNP: rs62637580
Type: single nucleotide variant
Location: chr9:133352739 (GRCh38)
Gene constraint: LOEUF 1.559 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.62
Residue 181: a UniProt-annotated variant site (in mc4dn1; uncertain significance)

Full SURF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Leigh syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leigh syndrome (Orphanet):

Inheritance: Autosomal recessive, Mitochondrial inheritance, X-linked recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

SURF1 p.Phe181Cys Uncertain significance ★ ⚠ same residue
SURF1 p.Phe181Tyr Uncertain significance ★ ⚠ same residue
SURF1 p.Phe181fs Pathogenic ★ same residue
SURF1 c.106+1G>C Likely pathogenic ★★ same condition
SURF1 c.240+1G>T Pathogenic ★★ same condition
SURF1 c.324-11T>G Pathogenic/Likely pathogenic ★★ same condition
SURF1 c.516-2A>G Pathogenic ★★ same condition
SURF1 c.588+1G>C Pathogenic ★★ 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/surf1-p-phe181 (accessed [today's date]).

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