Is SURF1 p.Ser286Pro (c.856T>C) pathogenic?

SURF1 p.Ser286Pro (c.856T>C) is classified Conflicting classifications of pathogenicity in SURF1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-27). AlphaMissense: likely pathogenic (0.8599); Absent from gnomAD v4.1; Associated with mitochondrial complex IV deficiency, nuclear type 1.

What condition is associated with SURF1 p.Ser286Pro (c.856T>C)?

SURF1 p.Ser286Pro (c.856T>C) is associated with mitochondrial complex IV deficiency, nuclear type 1 (ClinVar).

How common is SURF1 p.Ser286Pro (c.856T>C) in the general population?

SURF1 p.Ser286Pro (c.856T>C) is absent from gnomAD v4.1 (gnomAD).

How is Isolated cytochrome C oxidase deficiency inherited?

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

What do computational predictors say about SURF1 p.Ser286Pro (c.856T>C)?

AlphaMissense predicts likely pathogenic (score 0.8599) — an in-silico prediction, not a clinical call.

SURF1 p.Ser286Pro

c.856T>C · rs2119079774 · VCV2413124

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8599 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

mitochondrial complex IV deficiency, nuclear type 1

Computational evidence

Protein change
AlphaMissense	0.8599	likely pathogenic
REVEL	0.76	pathogenic-leaning
SaProt	LLR -13.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -3.3, phastCons 0.17
Regional constraint	o/e 1.19	unconstrained · MANE · 4,537 bp · p 0.00027 · regional, not allelic
Overall
CADD	18.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SURF1
Protein: p.Ser286Pro
Coding: c.856T>C
MANE Select: NM_003172
dbSNP: rs2119079774
Type: single nucleotide variant
Location: chr9:133351960 (GRCh38)
Gene constraint: LOEUF 1.559 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.62
Residue 286: 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

mitochondrial complex IV deficiency, nuclear type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Isolated cytochrome C oxidase deficiency (Orphanet):

Inheritance: Autosomal recessive, Mitochondrial inheritance

Similar variants

SURF1 p.Ser286Ala Uncertain significance ★ ⚠ same residue
SURF1 p.Ser286= Likely benign ★ same residue
SURF1 c.240+1G>T Pathogenic ★★ same condition
SURF1 c.324-11T>G Pathogenic/Likely pathogenic ★★ same condition
SURF1 c.516-1G>A Pathogenic ★★ same condition
SURF1 c.588+1G>C Pathogenic ★★ same condition
SURF1 c.833+1G>A Pathogenic ★★ same condition
SURF1 p.Arg192Gln Pathogenic/Likely 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-ser286pro (accessed [today's date]).

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