Is DNAH8 p.Ser671Phe (c.2012C>T) pathogenic?

DNAH8 p.Ser671Phe (c.2012C>T) is classified Uncertain significance in DNAH8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-25). AlphaMissense: likely pathogenic (0.9157); Very rare (popmax 0.00673%, eas).

How common is DNAH8 p.Ser671Phe (c.2012C>T) in the general population?

DNAH8 p.Ser671Phe (c.2012C>T) is very rare (popmax 0.00673%, eas) (gnomAD).

What do computational predictors say about DNAH8 p.Ser671Phe (c.2012C>T)?

AlphaMissense predicts likely pathogenic (score 0.9157) — an in-silico prediction, not a clinical call.

DNAH8 p.Ser671Phe

c.2012C>T · VCV4242821

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9157 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00673%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.9157	likely pathogenic
REVEL	0.242	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	Δ0.35	donor loss · deltas
Pangolin	Δ0.32	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 131 kb · p 0.0001 · regional, not allelic
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S454F vs ClinVar S671F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00673% East Asian · 3/44,566 alleles

Filtering AF 0.00179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000895%

Overall 0.000188% 3/1,595,982 alleles · very rare exomes 2/1,443,818 · genomes 1/152,164 · joint denominator

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: DNAH8
Protein: p.Ser671Phe
Coding: c.2012C>T
MANE Select: NM_001206927
Type: single nucleotide variant
Location: chr6:38778437 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 (gnomAD)

Full DNAH8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAH8 c.10963-1G>A Likely pathogenic ★★ same type
DNAH8 c.11563+1G>T Likely pathogenic ★★ same type
DNAH8 c.2664+2T>C Likely pathogenic ★★ same type
DNAH8 c.5734-1G>T Likely pathogenic ★★ same type
DNAH8 p.Arg1090Ter Pathogenic/Likely pathogenic ★★ same type
DNAH8 p.Arg207Ter Pathogenic/Likely pathogenic ★★ same type
DNAH8 p.Arg2878Ter Pathogenic ★★ same type
DNAH8 p.Arg4166Ter Pathogenic/Likely pathogenic ★★ 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/dnah8-p-ser671phe (accessed [today's date]).

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