Is PHGDH p.Ser409= (c.1227C>T) pathogenic?

PHGDH p.Ser409= (c.1227C>T) is classified Likely benign in PHGDH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). Ultra-rare (popmax 0.0101%, amr); Associated with PHGDH deficiency.

What condition is associated with PHGDH p.Ser409= (c.1227C>T)?

PHGDH p.Ser409= (c.1227C>T) is associated with PHGDH deficiency (ClinVar).

How common is PHGDH p.Ser409= (c.1227C>T) in the general population?

PHGDH p.Ser409= (c.1227C>T) is ultra-rare (popmax 0.0101%, amr) (gnomAD).

PHGDH p.Ser409=

c.1227C>T · rs768582720 · VCV1586716

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, amr)

Conditions

PHGDH deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.53	GERP -1.5
Overall
CADD	7.285	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0101% Admixed American · 6/59,676 alleles

Filtering AF 0.0043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00296%

Overall 0.000435% 7/1,610,446 alleles · ultra-rare exomes 5/1,458,186 · genomes 2/152,260 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0101%	9,946
Remaining individualsnot grpmax-eligible	0.0016%	62,320

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: PHGDH
Protein: p.Ser409=
Coding: c.1227C>T
MANE Select: NM_006623
dbSNP: rs768582720
Type: single nucleotide variant
Location: chr1:119742824 (GRCh38)
Gene constraint: LOEUF 1.155 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.06 · 21 PDB

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

Disease context

PHGDH deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHGDH c.1078+1G>A Likely pathogenic ★★ same condition
PHGDH c.138+1G>T Likely pathogenic ★★ same condition
PHGDH c.139-2A>G Likely pathogenic ★★ same condition
PHGDH c.290+2T>C Pathogenic/Likely pathogenic ★★ same condition
PHGDH c.357-1G>A Pathogenic/Likely pathogenic ★★ same condition
PHGDH c.412-1G>C Likely pathogenic ★★ same condition
PHGDH c.643+1G>A Likely pathogenic ★★ same condition
PHGDH p.Arg135Trp 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/phgdh-p-ser409 (accessed [today's date]).

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